bluuebunny/crossref_metadata_2025 huggingface dataset:
Excitability changes in human corticospinal projections to muscles moving hand and fingers while viewing a reaching and grasping action
Authors: Montagna Marcella , Cerri Gabriella , Borroni Paola , Baldissera Fausto
Published: September 2005

Excitability of the H‐reflex in the relaxed flexor digitorum superficialis (FDS) muscle was tested in five subjects observing a reaching and grasping action. The amplitude of the FDS H‐reflex was modulated with a peak occurring during the hand‐opening phase of the observed movement. When the H‐reflex was facilitated by subliminal transcranial magnetic stimulation (TMS), the modulation was larger than for an unconditioned reflex of similar size. This suggests that the primary motor cortex excitability is modulated by action viewing and reasonably causes the motoneuronal excitability changes. Moreover, motor evoked potentials (MEPs) were elicited by supraliminal TMS in FDS, flexor carpi radialis (FCR) and first dorsal interosseus (FDI) when observing the same movement. MEP amplitude was modulated in FDS with the same time‐course as the H‐reflex, the peak excitability occurring during hand opening. In FDI, however, the maximal excitability occurred during finger closing while in FCR no correlation was found with the movement phases. Finally the EMG activity of FCR, FDS and FDI was recorded while the subjects were actually performing a grasping movement similar to the one observed. In all subjects and for each muscle there was a clear‐cut correspondence between the time‐course of the excitability modulation of MEPs and the temporal pattern of EMG recruitment. In conclusion, the present study suggests that ‘motor resonance’ subliminally activates the same motor pathways that would be overtly recruited in each observer when actually performing the observed movement, reproducing the personal strategy adopted in the same task.
The anti‐epileptic actions of neuropeptide Y in the hippocampus are mediated by Y2 and not Y5 receptors
Authors: El Bahh Bouchaïb , Balosso Silvia , Hamilton Trevor , Herzog Herbert , Beck‐Sickinger Annette G. , Sperk Günther , Gehlert Donald R. , Vezzani Annamaria , Colmers William F.
Published: September 2005

Neuropeptide Y (NPY) potently inhibits glutamate release and seizure activity in rodent hippocampus in vitro and in vivo, but the nature of the receptor(s) mediating this action is controversial. In hippocampal slices from rats and several wild‐type mice, a Y2‐preferring agonist mimicked, and the Y2‐specific antagonist BIIE0246 blocked, the NPY‐mediated inhibition both of glutamatergic transmission and of epileptiform discharges in two different slice models of temporal lobe epilepsy, stimulus train‐induced bursting (STIB) and 0‐Mg2+ bursting. Whereas Y5 receptor‐preferring agonists had small but significant effects in vitro, they were blocked by BIIE0246, and a Y5 receptor‐specific antagonist did not affect responses to any agonist tested in any preparation. In slices from mice, NPY was without effect on evoked potentials or in either of the two slice seizure models. In vivo, intrahippocampal injections of Y2‐ or Y5‐preferring agonists inhibited seizures caused by intrahippocampal kainate, but again the Y5 agonist effects were insensitive to a Y5 antagonist. Neither Y2‐ nor Y5‐preferring agonists affected kainate seizures in mice. A Y5‐specific antagonist did not displace the binding of two different NPY ligands in WT or mice, whereas all NPY binding was eliminated in the mouse. Thus, we show that Y2 receptors alone mediate all the anti‐excitatory actions of NPY seen in the hippocampus, whereas our findings do not support a role for Y5 receptors either in vitro or in vivo. The results suggest that agonists targeting the Y2 receptor may be useful anticonvulsants.
Fyn kinase‐mediated phosphorylation of NMDA receptor NR2B subunit at Tyr1472 is essential for maintenance of neuropathic pain
Authors: Abe Tetsuya , Matsumura Shinji , Katano Tayo , Mabuchi Tamaki , Takagi Kunio , Xu Li , Yamamoto Akitsugu , Hattori Kotaro , Yagi Takeshi , Watanabe Masahiko , Nakazawa Takanobu , Yamamoto Tadashi , Mishina Masayoshi , Nakai Yoshihide , Ito Seiji
Published: September 2005

Despite abundant evidence implicating the importance of N‐methyl‐d‐aspartate (NMDA) receptors in the spinal cord for pain transmission, the signal transduction coupled to NMDA receptor activation is largely unknown for the neuropathic pain state that lasts over periods of weeks. To address this, we prepared mice with neuropathic pain by transection of spinal nerve L5. Wild‐type, NR2A‐deficient, and NR2D‐deficient mice developed neuropathic pain; in addition, phosphorylation of NR2B subunits of NMDA receptors at Tyr1472 was observed in the superficial dorsal horn of the spinal cord 1 week after nerve injury. Neuropathic pain and NR2B phosphorylation at Tyr1472 were attenuated by the NR2B‐selective antagonist CP‐101,606 and disappeared in mice lacking Fyn kinase, a Src‐family tyrosine kinase. Concomitant with the NR2B phosphorylation, an increase in neuronal nitric oxide synthase activity was visualized in the superficial dorsal horn of neuropathic pain mice by NADPH diaphorase histochemistry. Electron microscopy showed that the phosphorylated NR2B was localized at the postsynaptic density in the spinal cord of mice with neuropathic pain. Indomethacin, an inhibitor of prostaglandin (PG) synthesis, and PGE receptor subtype EP1‐selective antagonist reduced the NR2B phosphorylation in these mice. Conversely, EP1‐selective agonist stimulated Fyn kinase‐dependent nitric oxide formation in the spinal cord. The present study demonstrates that Tyr1472 phosphorylation of NR2B subunits by Fyn kinase may have dual roles in the retention of NMDA receptors in the postsynaptic density and in activation of nitric oxide synthase, and suggests that PGE2 is involved in the maintenance of neuropathic pain via the EP1 subtype.
Biotic resistance to plant invasions? Native herbivores prefer non‐native plants
Authors: Parker John D. , Hay Mark E.
Published: September 2005

In contrast to expectations of the enemy release hypothesis, but consistent with the notion of biotic resistance, we found that native generalist crayfishes preferred exotic over native freshwater plants by a 3 : 1 ratio when plants were paired by taxonomic relatedness. Native crayfishes also preferred exotic over native plants when tested across 57 native and 15 exotic plants found growing sympatrically at 11 sites throughout the southeastern USA. Exotic grass carp that share little evolutionary history with most of these plants exhibited no preference for native vs. exotic species. Analyses of three terrestrial data sets showed similar patterns, with native herbivores generally preferring exotic plants, while exotic herbivores rarely exhibited a preference. Thus, exotic plants may escape their coevolved herbivores only to be preferentially consumed by the native generalist herbivores in their new ranges, suggesting that native herbivores may provide biotic resistance to plant invasions.
Magnitude and variability of process rates in fungal diversity‐litter decomposition relationships
Authors: Dang Christian K. , Chauvet Eric , Gessner Mark O.
Published: September 2005

There is compelling evidence that losses in plant diversity can alter ecosystem functioning, particularly by reducing primary production. However, impacts of biodiversity loss on decomposition, the complementary process in the carbon cycle, are highly uncertain. By manipulating fungal decomposer diversity in stream microcosm experiments we found that rates of litter decomposition and associated fungal spore production are unaffected by changes in decomposer diversity under benign and harsher environmental conditions. This result calls for caution when generalizing outcomes of biodiversity experiments across systems. In contrast to their magnitude, the variability of process rates among communities increased when species numbers were reduced. This was most likely caused by a portfolio effect (i.e. statistical averaging), with the uneven species distribution typical of natural communities tending to weaken that effect. Curbing species extinctions to maintain ecosystem functioning thus can be important even in situations where process rates are unaffected.
Identifying the impact of diabetes research
Authors: Hanney S. R. , Home P. D. , Frame I. , Grant J. , Green P. , Buxton M. J.
Published: September 2005

Aims  Assessment of the impact of health research is a growing but problematic field. We examined how a combination of approaches might together inform assessment of the impact of a body of diabetes research published in 1981 and help identify factors behind success.

Methods  Three broad approaches were applied to the work of one team leader of acknowledged influence. Standard bibliographic analysis was complemented by a second approach which categorized the importance of the primary publications to the papers citing them, in four domains. In parallel, a third approach involved qualitative assessment using surveys, critical pathway analysis by, and interviews of, co‐authors and external experts. Extending the approach incorporated key additional publications from other years.

Results  In 1981, the team leader published 29 papers. Citations to these 29 first generation papers varied from 1 to 76 and resulted in 799 second generation papers. Citations to these produced 12 891 third generation papers. Analysis of second generation papers suggested the cited first generation paper was thought to be of considerable or essential significance in only 9% of cases. While much research made little impact, qualitative analysis included a wealth of information, sometimes missed by standard bibliographic techniques, on where the identified research influenced important streams of clinical development. Analysis covered major research studies (such as the Diabetes Control and Complications Trial), insulin pump therapy, and career development of co‐authors.

Conclusions  Understanding the impact of research requires multiple approaches. With refinement, these techniques could be employed more widely and potentially could inform research policy.
Long‐term treatment experience in a subject with Dunnigan‐type familial partial lipodystrophy: efficacy of rosiglitazone
Authors: Lüdtke A. , Heck K. , Genschel J. , Mehnert H. , Spuler S. , Worman H. J. , Schmidt H. H.‐J.
Published: September 2005

Dunnigan‐type familial partial lipodystrophy (FPLD) is caused by mutations in LMNA, the gene that encodes nuclear lamins A and C. FPLD is characterized by peripheral fat loss, excess central adiposity, insulin resistance, and hyperlipidaemia, which are difficult to treat. We present our 2 years’ experience of treatment with rosiglitazone in a subject with FPLD. Insulin requirement decreased significantly from 240 IU/day to 76 IU/day (range 20–240 IU/day) and serum triglyceride concentration was lowered from 13.7 ± 14.4 mmol/l to 4.5 ± 4.3 mmol/l and remained stable. Mean HbA1c prior to rosiglitazone therapy was 9.4 ± 1.32% and decreased to 7.4 ± 0.6% during therapy with rosiglitazone. This case demonstrates the benefits of PPARγ‐agonists on glycaemic control and dyslipidaemia in a patient with FPLD. This in turn implies that PPARγ may play a pathophysiological role in FPLD.
Prevalence and risk factors for asymptomatic bacteriuria in women with Type 2 diabetes mellitus
Authors: Ishay A. , Lavi I. , Luboshitzky R.
Published: September 2005

Aims  Asymptomatic bacteriuria (ASB) has been considered as a complication in diabetic women. The reported data on the prevalence and various risk factors for ASB appear to be conflicting. Consequently, we investigated the prevalence and major risk factors of ASB in women with Type 2 diabetes mellitus.

Methods  A total of 411 non‐pregnant women (aged 59.6 ± 10.8 years) with Type 2 diabetes, and 160 women without diabetes (aged 53.3 ± 15.1 years) assigned as controls, attending an outpatient endocrine clinic in a university‐affiliated teaching hospital, were included. All participating women were interviewed and screened for the presence of ASB. In all participants, fasting blood glucose, HbA1c and renal function were measured. Complications of diabetes were also assessed.

Results  Of the 411 diabetic women, 25 (6.1%) had ASB, compared with four of 160 (2.5%) in control women (P = 0.07). Independent risk factors for the presence of ASB were albuminuria > 150 mg/24 h [odds ratio (OR) 4.96 (95% CI 1.64–15.0, P = 0.005)] and serum creatinine [OR 3.5 (95% CI 1.4–8.8, P = 0.008)]. No significant association was evident with age, BMI, duration of disease, glycaemic control assessed by HbA1c or chronic complications of diabetes, namely macrovascular disease, neuropathy and retinopathy.

Conclusions  Women with Type 2 diabetes are not at higher risk of developing ASB than non‐diabetic women. Independent and significant risk factors for ASB are macroalbuminuria and serum creatinine. The low prevalence of ASB found in this study may be as a result of the ethnic origin of these women and the circumcised state of their partners.
Regression Models with Data‐based Indicator Variables*
Authors: Hendry David F. , Santos Carlos
Published: September 2005

Ordinary least squares estimation of an impulse‐indicator coefficient is inconsistent, but its variance can be consistently estimated. Although the ratio of the inconsistent estimator to its standard error has a t‐distribution, that test is inconsistent: one solution is to form an index of indicators. We provide Monte Carlo evidence that including a plethora of indicators need not distort model selection, permitting the use of many dummies in a general‐to‐specific framework. Although White's (1980) heteroskedasticity test is incorrectly sized in that context, we suggest an easy alteration. Finally, a possible modification to impulse ‘intercept corrections’ is considered.
Leaning into the Wind: A Structural VAR Investigation of UK Monetary Policy*
Authors: Mountford Andrew
Published: September 2005

This paper adapts Uhlig's [Journal of Monetary Economics (2005) forthcoming] sign restriction identification methodology to investigate the effects of UK monetary policy using a structural vector autoregression (VAR). It shows that shocks which can reasonably be described as monetary policy shocks have played only a small role in the total variation of UK monetary and macroeconomic variables. Most of the variation in UK monetary variables has been due to their systematic reaction to other macroeconomic shocks, namely non‐monetary aggregate demand, aggregate supply, and oil price shocks. We also find, without imposing any long run identifying restrictions, that aggregate supply shocks have permanent effects on output.
Technology, Labour Characteristics and Wage‐productivity Gaps*
Authors: Ilmakunnas Pekka , Maliranta Mika
Published: September 2005

We use plant‐level employer–employee data in production functions and wage equations to examine whether wages are based on productivity. We use a stepwise procedure to find out how the results are influenced by the kind of data that is available. The models include shares of employee groups based on age, level and field of education, and sex. The gap between the age‐related wage and productivity effects increases with age. Education increases productivity, but wage under‐compensates productivity especially for those with the highest level of non‐technical education. For women the results depend greatly on the specification and method used.
Testing the Exogeneity of Argentine Devaluation and Default Risks in Retrospect*
Authors: Ahumada Hildegart A. , Garegnani Maria Lorena
Published: September 2005

This paper studies the relationship between devaluation and default risks during Argentina's convertibility regime. Before default and devaluation occurred, a harder variant of the currency regime was under discussion. An often‐suggested argument among the supporters of dollarization was that the probability of default could have been reduced by removing fears of devaluation. For this to be true, default risk must be dependent on the devaluation risk. Long‐run relationships and ‘exogeneity’ are examined using a ‘cointegrating vector’ system approach. The results show that only devaluation risk can be modelled on default risk. No empirical evidence is found in favour of dollarization. Moreover, these conclusions are maintained when the information set is expanded to include the Latin American risk and Argentine macroeconomic variables.
Practical Problems with Reduced‐rank ML Estimators for Cointegration Parameters and a Simple Alternative*
Authors: Brüggemann Ralf , Lütkepohl Helmut
Published: September 2005

Johansen's reduced‐rank maximum likelihood (ML) estimator for cointegration parameters in vector error correction models is known to produce occasional extreme outliers. Using a small monetary system and German data we illustrate the practical importance of this problem. We also consider an alternative generalized least squares (GLS) system estimator which has better properties in this respect. The two estimators are compared in a small simulation study. It is found that the GLS estimator can indeed be an attractive alternative to ML estimation of cointegration parameters.
Long‐term effect of bone marrow transplantation in adult‐onset adrenoleukodystrophy
Authors: Hitomi T. , Mezaki T. , Tomimoto H. , Ikeda A. , Shimohama S. , Okazaki T. , Uchiyama T. , Shibasaki H.
Published: September 2005

We report a long‐term outcome of motor function in a patient with adult‐onset adrenoleukodystrophy after bone marrow transplantation (BMT). Clinically motor function gradually improved and became almost normal in 2 years after BMT. Serial transcranial magnetic stimulation showed gradual improvement of central motor conduction until 1 year after BMT, and then it became stable. Central motor conduction time and motor threshold were useful for monitoring the central motor function in this patient.
Cholinergic treatment of amnesia following basal forebrain lesion due to aneurysm rupture – an open‐label pilot study
Authors: Benke T. , Köylü B. , Delazer M. , Trinka E. , Kemmler G.
Published: September 2005

Impairments of memory are often found after rupture and repair of aneurysms leading to a basal forebrain lesion. This open study investigated whether cholinergic substitution therapy may be a treatment option. The effect of donepezil, a cholinesterase inhibitor on memory functions was tested in an open‐label, exploratory study in 11 patients with a chronic amnestic syndrome from a ruptured and repaired aneurysm of the anterior communicating artery (seven patients), the anterior cerebral (two) or the pericallosal artery (two). Mean time since onset was 75.4 months. Memory was evaluated at baseline and consecutively after 4 weeks of 5 mg donepezil daily, 8 weeks of 10 mg donepezil, and 4 weeks after drug discontinuation. Memory functions were assessed using the California Verbal Learning Test and compared with a matched group of normal, untreated controls. Tests of attention and of executive functions were also administered. Donepezil was well tolerated. Strong group effects were found at baseline and at all follow‐up measurements showing profound impairments of memory functions in the patient group. Within patient statistics showed significant improvements of short and long delay free recall scores during the treatment period, both with 5 and 10 mg donepezil daily, whereas attentional and executive functions improved only non‐significantly. Memory functions decreased after drug discontinuation. Repeated test administration in the control group also showed an increase of memory scores which was minor when compared with the performance change in the patient group. Donepezil may improve episodic memory functions in patients suffering from a chronic amnestic syndrome caused by rupture and repair of aneurysms of the anterior communicating, the anterior cerebral or the pericallosal artery. Future doubled‐blind, placebo‐controlled trials are warranted to confirm these findings.
Frequency of early and late‐onset dementias in a Japanese memory disorders clinic
Authors: Yokota O. , Sasaki K. , Fujisawa Y. , Takahashi J. , Terada S. , Ishihara T. , Nakashima H. , Kugo A. , Ata T. , Ishizu H. , Kuroda S.
Published: September 2005

The aim of this study was to compare the diagnostic profiles of patients with early (age <65 years) and late (age ≥65 years) onset of dementia in a memory disorders clinic in Japan. A total of 512 consecutive memory clinic patients were evaluated using clinical information and results of examinations. Diagnosis of dementia was made according to DSM‐III‐R, and that of subtypes according to standard diagnostic criteria. A total of 464 patients met the criteria for dementia. Amongst late‐onset patients (n = 430), Alzheimer's disease (AD) (48.1%) was the most frequent cause of dementia, followed by AD with cerebrovascular disease (CVD) (31.4%), vascular dementia (VaD) (9.1%), dementia with Lewy bodies (DLB) (3.7%), frontotemporal lobar degeneration (FTLD) (1.6%), and others (5.8%). On the contrary, amongst early onset patients (n = 34), the most common dementia diagnosis was AD (38.2%), followed by VaD (23.5%), FTLD (14.7%), AD with CVD (5.9%), DLB (2.9%), and others (17.6%). FTLD and VaD were significantly more common in the early onset group. All patients, but one, with DLB and Parkinson's disease dementia were late‐onset. The relative frequencies of AD, VaD, and DLB in our series are consistent with epidemiologic findings in several Western countries; however, the frequency of FTLD is not consistent with the previous findings presenting high frequency in late‐onset patients in some Western countries.
Efficacy of oral naratriptan in the treatment of menstrually related migraine
Authors: Massiou H. , Jamin C. , Hinzelin G. , Bidaut‐Mazel C. ,   The French Naramig Collaborative Study Group
Published: September 2005

The aim of this study was to investigate the efficacy of orally administered 2.5 mg naratriptan in the treatment of menstrually related migraine (MRM). A high percentage of women suffering from migraine report increased frequency of attacks in association with menstruation that may be more severe, of longer duration and more difficult to treat than at other times. This was a phase IIIb, randomized, double‐blind, placebo‐controlled clinical trial. Subjects were given either 2.5 mg naratriptan or placebo to treat a single MRM episode, defined as starting between days −2 and +4 relative to the start of menstruation. The primary efficacy measure was the percentage of subjects who were free of pain 4 h after treatment, the absence of pain at 30 min, 1 and 2 h being secondary efficacy measures. Other secondary measures were the absence of associated symptoms, sustained headache relief 24 h after a single dose of the study medication, recourse to a second dose of study medication or escape medication, pain intensity 4–24 h after first treatment, the ability to carry out work or daily activities, and patient satisfaction. Adverse events were also monitored. A total of 275 women were enrolled in the trial and 229 (115 naratriptan group, 114 placebo group) provided data on the effects of the study medication on MRM. A higher percentage of subjects in the naratriptan group (58%) reported complete pain relief 4 h after medication than in the placebo group (30%) (P < 0.001). Significant differences between the naratriptan and placebo groups and in favor of naratriptan were also found for: total pain relief at 2 h (P = 0.004), sustained pain‐free response within 4–24 h (P < 0.001), absence of all associated symptoms at 2 and 4 h (P = 0.004), ability to work and carry out daily activities at 2 h (P = 0.036), and patient overall satisfaction (P < 0.001). Three adverse events were recorded that might potentially be attributable to naratriptan. Naratriptan given orally at a dose of 2.5 mg is effective in the acute treatment of MRM as early as 2 h after treatment.
Ethnic nationalism, evolutionary psychology and Genetic Similarity Theory*
Authors: Rushton J. Philippe
Published: September 2005

Abstract.Genetic Similarity Theory extends Anthony D. Smith's theory of ethno‐symbolism by anchoring ethnic nepotism in the evolutionary psychology of altruism. Altruism toward kin and similar others evolved in order to help replicate shared genes. Since ethnic groups are repositories of shared genes, xenophobia is the ‘dark side’ of human altruism. A review of the literature demonstrates the pull of genetic similarity in dyads such as marriage partners and friendships, and even large groups, both national and international. The evidence that genes incline people to prefer others who are genetically similar to themselves comes from studies of social assortment, differential heritabilities, the comparison of identical and fraternal twins, blood tests, and family bereavements. DNA sequencing studies confirm some origin myths and disconfirm others; they also show that in comparison to the total genetic variance around the world, random co‐ethnics are related to each other on the order of first cousins.
Sub‐state nationalism and the left–right divide: critical junctures in the formation of nationalist labour movements in Belgium*
Authors: Erk Jan
Published: September 2005

Abstract. Despite their similar political agendas, sub‐state nationalist movements in the industrialised West align themselves on different positions along the left–right spectrum. Through an analysis of Belgian sub‐state nationalist movements, this article proposes an explanation for this phenomenon by focusing on critical junctures. In particular, the focus is on the difference between Walloon and Flemish nationalist labour movements. Walloon nationalism has historically been led by socialist trade unions, while Catholic trade unions form a core part of the Flemish nationalist movement. The article seeks to explain this pattern by analysing the critical political alliances formed during the introduction of universal suffrage. The elections of 1894 established socialists as the dominant force in Wallonia and Catholics as dominant in Flanders. The emerging pillarised social structure ensured the reinforcement of the initial choices.
Tiny transmitters of nationalist and colonial ideology: the postage stamps of Portugal and its Empire*
Authors: Cusack Igor
Published: September 2005

Abstract. Postage stamps may be seen as tiny transmitters of the dominant ideologies of the state destined for the imagined community of the nation. The issuing of stamps, starting in the nineteenth century, and the postal reforms that accompanied this, greatly contributed to the ‘communicative efficiency’ of national communities and made a significant contribution to nation‐building. The imagery of stamps promotes the dominant discourses of a particular nationalism, recalls historical triumphs and myths and defines the national territory in maps or landscapes. Issuing authorities also print stamps for sale to a large, epistemic community of philatelists and this has been of particular importance to many colonial authorities and impoverished post‐colonial states. This article addresses these themes by focusing on the stamps of Portugal and its Empire. The representation of images of women on the stamps of the Portuguese monarchy, the Republic, the Estado Novo and the modern Portuguese Republic, as well as in the former Empire, all confirm the patriarchal construction of Portuguese nationalism as well as a focus on the ‘great discoveries’.
Contextualising ‘Turkification’: nation‐building in the late Ottoman Empire, 1908–18*
Authors: Ülker Erol
Published: September 2005

Abstract.This article offers an analytical framework for understanding the peculiarities of the Ottoman Empire's nationality policies in the second constitutional period (1908–18). It will examine the extent to which the nationality policies of the Young Turks can be perceived as a nation‐building project, and question whether it is reasonable to apply the term ‘Turkification’ to these policies. The primary goal of the paper in this context is to identify how and to what degree a nationalist outlook shaped imperial polices of the late Ottoman Empire. Engaging in a critical dialogue with the existing historiography, the article argues that ‘Turkification’ should be conceptualised solely as a project of nation‐building in the multiethnic Ottoman Empire. It was only one of the policies employed by the imperial elite and it coexisted with other imperial policies ranging from centralisation to decentralisation, assimilation to dissimilation and integration to homogenisation. The paper concludes by contending that only by contextualising and understanding this complexity and only by taking geographical variations into account can the peculiarity of ‘Turkification’ be grasped.
Regulation of expression of the novel IL‐1 receptor family members in the mouse brain
Authors: Andre Ralph , Lerouet Dominique , Kimber Ian , Pinteaux Emmanuel , Rothwell Nancy J.
Published: September 2005

Members of the interleukin‐1 (IL‐1) family of cytokines are key mediators in the regulation of host defence responses and the development of inflammation in response to acute and chronic injury to the brain. Two major agonists, IL‐1α and IL‐1β, bind to a membrane receptor complex composed of the type‐1 IL‐1 receptor (IL‐1RI) and the accessory protein (IL‐1RAcP). The discovery of new orphan members of the IL‐1 receptor superfamily (including ST2/T1, IL‐1Rrp2, TIGIRR1 and ‐2, SIGGIR, IL‐18Rα and IL‐18Rβ) has increased speculation that alternative IL‐1 ligands signalling pathways exist in the brain. We demonstrate here that all the IL‐1R‐like orphan receptors are expressed by many brain cell types including astrocytes, microglia, oligodendrocytic progenitor cells and neurons. IL‐18Rβ expression was significantly increased in response to treatment of mixed glia with bacterial lipopolysaccharide (LPS) in vitro, whereas expression of IL‐1Rrp2 and TIGIRR1 was reduced. Furthermore, IL‐18Rβ, IL‐1Rrp2, but not TIGIRR1 expression, was increased in the brain in vivo in response to peripheral administration of LPS or middle cerebral artery occlusion (MCA). These results suggest possible roles for newly identified members of the IL‐1 receptor family in CNS diseases.
Astrocytes as antigen‐presenting cells: expression of IL‐12/IL‐23
Authors: Constantinescu Cris S. , Tani Marie , Ransohoff Richard M. , Wysocka Maria , Hilliard Brendan , Fujioka Toshiki , Murphy Sean , Tighe Patrick J. , Sarma Jayasri Das , Trinchieri Giorgio , Rostami Abdolmohamad
Published: September 2005

Interleukin‐12 (IL‐12, p70) a heterodimeric cytokine of p40 and p35 subunits, important for Th1‐type immune responses, has been attributed a prominent role in multiple sclerosis (MS) and its animal model, experimental autoimmune encephalomyelitis (EAE). Recently, the related heterodimeric cytokine, IL‐23, composed of the same p40 subunit as IL‐12 and a unique p19 subunit, was shown to be involved in Th1 responses and EAE. We investigated whether astrocytes and microglia, CNS cells with antigen‐presenting cell (APC) function can present antigen to myelin basic protein (MBP)‐reactive T cells, and whether this presentation is blocked with antibodies against IL‐12/IL‐23p40. Interferon (IFN)‐γ‐treated APC induced proliferation of MBP‐reactive T cells. Anti‐IL‐12/IL‐23p40 antibodies blocked this proliferation. These results support and extend our previous observation that astrocytes and microglia produce IL‐12/IL‐23p40. Moreover, we show that stimulated astrocytes and microglia produce biologically active IL‐12p70. Because IL‐12 and IL‐23 share p40, we wanted to determine whether astrocytes also express IL‐12p35 and IL‐23p19, as microglia were already shown to express them. Astrocytes expressed IL‐12p35 mRNA constitutively, and IL‐23 p19 after stimulation. Thus, astrocytes, under inflammatory conditions, express all subunits of IL‐12/IL‐23. Their ability to present antigen to encephalitogenic T cells can be blocked by neutralizing anti‐IL‐12/IL‐23p40 antibodies.
Identification, expression and functional characterization of the GRAL gene
Authors: Li Zhihua , Wang Bingwei , Wu Xuefei , Cheng Shi‐Yuan , Paraoan Luminita , Zhou Jiawei
Published: September 2005

The glial cell line‐derived neurotrophic factor (GDNF) family is a group of neurotrophic factors with diverse biological functions. Members of the GDNF family exert their functions by interacting with a specific GDNF family receptor α (GFRα) and activation of the cRET. Here we report the identification and characterization of GDNF receptor‐alpha‐like (GRAL) gene. Sequence analysis indicated that GRAL is a distant homolog of the GFRα family, with 30% of its amino acid sequence identical to that of GFRα‐3. There are two splice variants of GRAL: the full‐length form (GRAL‐A) represented by a 2080 bp mRNA and a short form (GRAL‐B) represented by a 1833 bp mRNA. In adult mouse, GRAL transcripts have been found primarily in the CNS. In the developing mouse brain, the mRNA level of GRAL in the cerebrocortex and hippocampus reached a maximum at birth and declined afterwards. GRAL‐A protein was localized predominantly in the plasma membrane. Overexpression of GRAL‐A protected PC12 cells and cultured hippocampal neurons from serum starvation‐induced cell apoptosis. The neuroprotective effect of GRAL was associated with marked inhibition of the Jun‐N‐terminal kinase signaling pathway. Our results suggest that GRAL belongs to a superfamily of GFRα and might take part in neuroprotection and brain development.
Induction of mitochondrial oxidative stress in astrocytes by nitric oxide precedes disruption of energy metabolism
Authors: Jacobson Jake , Duchen Michael R. , Hothersall John , Clark John B. , Heales Simon J. R.
Published: September 2005

Inhibition of the mitochondrial electron transport chain (ETC) ultimately limits ATP production and depletes cellular ATP. However, the individual complexes of the ETC in brain mitochondria need to be inhibited by ∼ 50% before causing significant depression of ATP synthesis. Moreover, the ETC is the key site for the production of intracellular reactive oxygen species (ROS) and inhibition of one or more of the complexes of the ETC may increase the rate of mitochondrial ROS generation. We asked whether partial inhibition of the ETC, to a degree insufficient to perturb oxidative phosphorylation, might nonetheless induce ROS production. Chronic increase in mitochondrial ROS might then cause oxidative damage to the ETC sufficient to produce prolonged changes in ETC function and so compound the defect. We show that the exposure of astrocytes in culture to low concentrations of nitric oxide (NO) induces an increased rate of O2·− generation that outlasts the presence of NO. No effect was seen on oxygen consumption, lactate or ATP content over the 4–6 h that the cells were exposed to NO. These data suggest that partial ETC inhibition by NO may initially cause oxidative stress rather than ATP depletion, and this may subsequently induce irreversible changes in ETC function providing the basis for a cycle of damage.
Leptin induces a novel form of NMDA receptor‐dependent long‐term depression
Authors: Durakoglugil Murat , Irving Andrew J. , Harvey Jenni
Published: September 2005

It is becoming apparent that the hormone leptin plays an important role in modulating hippocampal function. Indeed, leptin enhances NMDA receptor activation and promotes hippocampal long‐term potentiation (LTP). Furthermore, obese rodents with dysfunctional leptin receptors display impairments in hippocampal synaptic plasticity. Here we demonstrate that under conditions of enhanced excitability (evoked in Mg2+‐free medium or following blockade of GABAA receptors), leptin induces a novel form of long‐term depression (LTD) in area CA1 of the hippocampus. Leptin‐induced LTD was markedly attenuated in the presence of D‐(‐)‐2‐Amino‐5‐Phosphonopentanoic acid (D‐AP5), suggesting that it is dependent on the synaptic activation of NMDA receptors. In addition, low‐frequency stimulus‐evoked LTD occluded the effects of leptin. In contrast, metabotropic glutamate receptors (mGluRs) did not contribute to leptin‐induced LTD as mGluR antagonists failed to either prevent or reverse this process. The signalling mechanisms underlying leptin‐induced LTD were independent of the Ras‐Raf‐mitogen‐activated protein kinase signalling pathway, but were markedly enhanced following inhibition of either phosphoinositide 3‐kinase or protein phosphatases 1 and 2A. These data indicate that under conditions of enhanced excitability, leptin induces a novel form of homosynaptic LTD, which further underscores the proposed key role for this hormone in modulating NMDA receptor‐dependent hippocampal synaptic plasticity.
Increased nuclear factor‐erythroid 2 p45‐related factor 2 activity protects SH‐SY5Y cells against oxidative damage
Authors: Cao Tracy T. , Ma Lei , Kandpal Geeta , Warren Lee , Hess J. Fred , Seabrook Guy R.
Published: September 2005

The ability of cells to control the balance between the generation and quenching of reactive oxygen species is important in combating potentially damaging effects of oxidative stress. One mechanism that cells use to maintain redox homeostasis is the antioxidant response pathway. Antioxidant response elements (AREs) are cis‐acting elements located in regulatory regions of antioxidant and phase II detoxification genes. Nuclear factor‐erythroid 2 p45‐related factor 2 (Nrf2) is a member of the Cap ‘n’ Collar family of transcription factors that binds to the ARE and regulates the transcription of specific ARE‐containing genes such as NAD(P)H:quinone oxidoreductase 1, glutamylcysteine synthetase and heme oxygenase. Activation of Nrf2 results in release from its negative repressor, Kelch‐like ECH‐associated protein 1 (Keap1), and allows Nrf2 to translocate into the nucleus to induce gene expression. In this study, we demonstrate that increasing Nrf2 activity by various methods, including chemical induction, Nrf2 overexpression or Keap1 siRNA knockdown, protects cells against specific types of oxidative damage. Cells were protected against 6‐hydroxydopamine‐ and 3‐morpholinosydnonimine‐mediated toxicity but not against 1‐methyl‐1‐4‐phenylpyridinium toxicity. As oxidative stress is a hallmark of several neurodegenerative disorders, including Parkinson's disease, pharmacological agents that selectively target the Keap1‐Nrf2 pathway may provide a novel neuroprotective strategy for the treatment of these diseases.
Spatio‐temporal activation of cyclic AMP response element‐binding protein, activity‐regulated cytoskeletal‐associated protein and brain‐derived nerve growth factor: a mechanism for pontine‐wave generator activation‐dependent two‐way active‐avoidance memory processing in the rat
Authors: Ulloor Jagadish , Datta Subimal
Published: September 2005

The present study explored possible physiological and molecular mechanisms of pontine‐wave (P‐wave) generator activation‐dependent memory processing in the rat using a two‐way active‐avoidance learning paradigm. The results show that learning training increased rapid eye movement sleep and activated brainstem cells in the P‐wave generator. During this period, there was a time‐dependent increase in phosphorylation of cAMP response element‐binding protein (CREB) in the dorsal hippocampus and amygdala and increased synthesis of activity‐regulated cytoskeletal‐associated protein (Arc) in the dorsal hippocampus, amygdala, frontal cortex and occipital cortex. Learning training also increased synthesis of brain‐derived nerve growth factor (BDNF) in the occipital cortex, amygdala and dorsal hippocampus at different time intervals. During this time, the levels of nerve growth factor did not change. The results also show that the increase in rapid eye movement sleep P‐wave density during the post‐training 3‐h recording session is positively correlated with the increased levels of phosphorylated CREB, BDNF and Arc in the dorsal hippocampus. These results suggest that memory processing of two‐way active‐avoidance learning may involve excitation of P‐wave‐generating cells in the brainstem and increased expression of phosphorylated CREB, Arc and BDNF in a time‐dependent manner in the forebrain. These dynamic changes in cellular and molecular features provide considerable insight into the mechanisms of the P‐wave generator activation‐dependent memory consolidation process.
Methamphetamine‐induced inhibition of mitochondrial complex II: roles of glutamate and peroxynitrite
Authors: Brown Jeffrey M. , Quinton Maria S. , Yamamoto Bryan K.
Published: September 2005

High‐dose methamphetamine (METH) is associated with long‐term deficits in dopaminergic systems. Although the mechanism(s) which contributes to these deficits is not known, glutamate and peroxynitrite are likely to play a role. These factors are hypothesized to inhibit mitochondrial function, increasing the free radical burden and decreasing neuronal energy supplies. Previous studies suggest a role for the mitochondrial electron transport chain (ETC) in mediating toxicity of METH. The purpose of the present studies was to determine whether METH administration selectively inhibits complex II of the ETC in rats. High‐dose METH administration (10 mg/kg every 2 h × 4) rapidly (within 1 h) decreased complex II (succinate dehydrogenase) activity by ∼20–30%. In addition, decreased activity of complex II–III, but not complex I–III, of the mitochondrial ETC was also observed 24 h after METH. This inhibition was not due to direct inhibition by METH or METH‐induced hyperthermia and was specific to striatal brain regions. METH‐induced decreases in complex II–III were prevented by MK‐801 and the peroxynitrite scavenger 5,10,15,20‐tetrakis (2,4,6‐trimethyl‐3,5‐sulphonatophenyl) porphinato iron III. These findings provide the first evidence that METH administration, via glutamate receptor activation and peroxynitrite formation, selectively alters a specific site of the ETC.
Modulation of the cannabinoid CB2 receptor in microglial cells in response to inflammatory stimuli
Authors: Maresz Katarzyna , Carrier Erica J. , Ponomarev Eugene D. , Hillard Cecilia J. , Dittel Bonnie N.
Published: September 2005

The cannabinoid system is known to be important in neuronal regulation, but is also capable of modulating immune function. Although the CNS resident microglial cells have been shown to express the CB2 subtype of cannabinoid receptor during non‐immune‐mediated pathological conditions, little is known about the expression of the cannabinoid system during immune‐mediated CNS pathology. To examine this question, we measured CB2 receptor mRNA expression in the CNS of mice with experimental autoimmune encephalomyelitis (EAE) and, by real‐time PCR, found a 100‐fold increase in CB2 receptor mRNA expression during EAE onset. We next determined whether microglial cells specifically express the CB2 receptor during EAE, and found that activated microglial cells expressed 10‐fold more CB2 receptor than microglia in the resting state. To determine the signals required for the up‐regulation of the CB2 receptor, we cultured microglial cells with combinations of γ‐interferon (IFN‐γ) and granulocyte) macrophage‐colony stimulating factor (GM‐CSF), which both promote microglial cell activation and are expressed in the CNS during EAE, and found that they synergized, resulting in an eight to 10‐fold increase in the CB2 receptor. We found no difference in the amount of the CB2 receptor ligand, 2‐arachidonylglycerol (2‐AG), in the spinal cord during EAE. These data demonstrate that microglial cell activation is accompanied by CB2 receptor up‐regulation, suggesting that this receptor plays an important role in microglial cell function in the CNS during autoimmune‐induced inflammation.
APP substitutions V715F and L720P alter PS1 conformation and differentially affect Aβ and AICD generation
Authors: Tesco Giuseppina , Ginestroni Andrea , Hiltunen Mikko , Kim Minji , Dolios Georgia , Hyman Bradley T. , Wang Rong , Berezovska Oksana , Tanzi Rudolph E.
Published: September 2005

The 37–43 amino acid Aβ peptide is the principal component of β‐amyloid deposits in Alzheimer's disease (AD) brain, and is derived by serial proteolysis of the amyloid precursor protein (APP) by β‐ and γ‐secretase. γ‐Secretase also cleaves APP at Val50 in the Aβ numbering (ε cleavage), resulting in the release of a fragment called APP intracellular domain (AICD). The aim of this study was to determine whether amino acid substitutions in the APP transmembrane domain differentially affect Aβ and AICD generation. We found that the APPV715F substitution, which has been previously shown to dramatically decrease Aβ40 and Aβ42 while increasing Aβ38 levels, does not affect in vitro generation of AICD. Furthermore, we found that the APPL720P substitution, which has been previously shown to prevent in vitro generation of AICD, completely prevents Aβ generation. Using a fluorescence resonance energy transfer (FRET) method, we next found that both the APPV715F and APPL720P substitutions significantly increase the distance between the N‐ and C‐terminus of presenilin 1 (PS1), which has been proposed to contain the catalytic site of γ‐secretase. In conclusion, both APPV715F and APPL720P change PS1 conformation with differential effects on Aβ and AICD production.
Controlled cortical impact injury affects dopaminergic transmission in the rat striatum
Authors: Wagner A. K. , Sokoloski J. E. , Ren D. , Chen X. , Khan A. S. , Zafonte R. D. , Michael A. C. , Dixon C. E.
Published: September 2005

The therapeutic benefits of dopamine (DA) agonists after traumatic brain injury (TBI) imply a role for DA systems in mediating functional deficits post‐TBI. We investigated how experimental TBI affects striatal dopamine systems using fast scan cyclic voltammetry (FSCV), western blot, and d‐amphetamine‐induced rotational behavior. Adult male Sprague–Dawley rats were injured by a controlled cortical impact (CCI) delivered unilaterally to the parietal cortex, or were naïve controls. Amphetamine‐induced rotational behavior was assessed 10 days post‐CCI. Fourteen days post‐CCI, animals were anesthetized and underwent FSCV with bilateral striatal carbon fiber microelectrode placement and stimulating electrode placement in the medial forebrain bundle (MFB). Evoked DA overflow was assessed in the striatum as the MFB was electrically stimulated at 60 Hz for 10 s. In 23% of injured animals, but no naïve animals, rotation was observed with amphetamine administration. Compared with naïves, striatal evoked DA overflow was lower for injured animals in the striatum ipsilateral to injury (p < 0.05). Injured animals exhibited a decrease in Vmax (52% of naïve, p < 0.05) for DA clearance in the hemisphere ipsilateral to injury compared with naïves. Dopamine transporter (DAT) expression was proportionally decreased in the striatum ipsilateral to injury compared with naïve animals (60% of naïve, p < 0.05), despite no injury‐related changes in vesicular monoamine transporter or D2 receptor expression (DRD2) in this region. Collectively, these data appear to confirm that the clinical efficacy of dopamine agonists in the treatment of TBI may be related to disruptions in the activity of subcortical dopamine systems.