bluuebunny/crossref_metadata_2025 huggingface dataset:
Pelvic pain caused by intraperitoneal Enterobius vermicularis (threadworm) ova with an associated systemic autoimmune reaction
Authors: Thomson John C.
Published: March 2004

Aim:  The aim of this paper, based on a case study was two‐fold; firstly to review the sites and gynecologic complications of ectopic Enterobius vermicularis and secondly study the autoimmune accompaniments of parasitic infestations.

Methods:  A case of intraperitoneal ectopic Enterobius vermicularis, with accompanying autoimmune signs and symptoms, is presented and its response to surgical and medical treatment described. A medical literature search was carried out into the subject of ectopic Enterobius vermicularis, particularly from the gynecologic perspective along with a study of autoimmune activation associated with parasitic infestation.

Results:  Pelvic pain was found to be caused by chronic inflammation from ectopic Enterobius vermicularis. This was treated both surgically and medically, with the surgical treatment proving to be inadequate but with a good response to immune modification. In the literature ectopic Enterobius vermicularis was found to be treatable surgically.

Conclusion:  Ectopic Enterobius vermicularis was found to create symptomatic inflammatory lesions that could be treated surgically and an associated autoimmune response treatable by immune modification.
Premature luteinization defined as progesterone estradiol ratio >1 on hCG administration day seems to adversely affect clinical outcome in long gonadotropin‐releasing hormone agonist cycles
Authors: Özçakir Hasan Tayfun , Levi Rafael , Tavmergen Erol , Göker Ege Nazan Tavmergen
Published: March 2004

Aim:  To examine the effect of premature luteinization on the outcomes in long gonadotropin‐releasing hormone agonist cycles.

Methods:  Two‐hundred and forty‐eight patients who had undergone assisted reproductive technology for infertility treatment between 2001 and 2002 were enrolled into the study. The patients were separated into two groups according to P/E2 ratios on human chorionic gonadotropin administration day. Group A consisted of the patients whose P/E2 ratio was 1 (n = 116) and Group B consisted of the patients with premature luteinization of which P/E2 ratio was > 1 (n = 132). The P/E2 ratio calculation was performed as follows: P (in ng/mL) ×†1,000/E2 (in pg/mL). The primary outcome measures included oocyte quality, fertilization rates and clinical pregnancy rates.

Results:  The mean number of mature oocytes retrieved in the groups were 9.5 ± 4.8 and 6.4 ± 3.6, respectively, and the difference was statistically significant (P < 0.05). Although the difference between the fertilization rates in Group A and Group B was not statistically significant (P > 0.05), the clinical pregnancy rates seemed to be affected adversely in the Group B patients with premature luteinization (41.4%versus 28%, respectively; P < 0.05).

Conclusion:  Premature luteinization, defined as P/E2 > 1 on human chorionic gonadotropin administration day, in long gonadotropin‐releasing hormone agonist cycles seems to adversely affect clinical outcome.
Non‐puerperal uterine inversion and uterine sarcoma (malignant mixed müllerian tumor): Report of an unusual case
Authors: Hanprasertpong Jitti , Wootipoom Virach , Hanprasertpong Tharangrut
Published: March 2004

A 45‐year‐old woman with a history of cervical cancer (stage IIa), who had received complete radiation treatment 16 years previously, presented with a huge mass protruding from her vaginal introitus. She had had the condition for about 1 week. Diagnosis was difficult, and she elected to have a diagnostic laparoscopic procedure plus tumor removal. The pathologic investigation revealed a malignant mixed müllerian tumor of the endometrium. Post‐operative course was uneventful. She underwent postoperative pelvic radiation. No recurrence was found during the 13 months follow up period. This rare case of chronic non‐puerperal uterine inversion due to malignant mixed müllerian tumor (MMMT) is herein reported.
Placental site trophoblastic tumor of the uterine cervix occurring from undetermined antecedent pregnancy
Authors: Soma Hiroaki , Okada Takahiko , Yoshinari Tsutomu , Furuno Atsuo , Yaguchi Seiichi , Tokoro Kazuo , Kato Hidenori
Published: March 2004

A cervical polyp complicated by severe hemorrhage was removed from a 43‐year‐old Japanese woman (gravida 0), who had undergone tubectomy on the right side 10 years previously. The polyp was diagnosed by immunohistochemical studies as placental site trophoblastic tumor of the cervix, but no metastatic foci were found in any other uterine site. The tumor was further demonstrated by PCR polymorphisms to possess two genomic DNA of the patient and her husband. Serum β‐hCG and urinary hCG titers were both low, which rapidly fell to 0.8 mIU/mL after a total hysterectomy and remained 0.2mIU/mL after dismission.

She has been uneventful for 3 years.
Analysis of HLA‐DRB1*0901‐binding HPV‐16 E7 helper T cell epitope†
Authors: Okubo Mitsuo , Saito Maki , Inoku Hiroki , Hirata Ranko , Yanagisawa Masami , Takeda Satoru , Kinoshita Katsuyuki , Maeda Hiroo
Published: March 2004

Aim:  This study sought to determine the human papillomavirus (HPV)‐16 E7 epitopes that would be presented by HLA‐DR molecules to CD4‐positive T cells in patients with cervical carcinoma.

Methods:  HLA‐DR binding assays were performed using HPV‐16 E7‐derived synthetic peptides and, after incubation with these DR‐binding peptides, helper T cell frequencies were analyzed in patients whose HLA and HPV genotypes were confirmed.

Results:  We determined that the E7d peptide, 61CDSTLRLCVQSTHVDIRTL80E, was bound by HLA‐DRB1*0901. An increased frequency (0.3–2.4%) of type 2 helper T cell responses was found in HLA‐DRB1*0901‐positive patients with cervical dysplasia and carcinoma. We found that when IL‐12 was combined with E7d‐peptide stimulation in vitro, the frequency of type 1 helper T cell responses also increased in patients with carcinoma.

Conclusion:  Thus HPV‐16 E7d peptide as an HLA‐DRB1*0901‐restricted helper T cell epitope might usefully be incorporated into an understanding of the immunological mechanism and immunotherapy for this disease.
Lipopolysaccharide administration enhances hypoxic‐ischemic brain damage in newborn rats
Authors: Yang Li , Sameshima Hiroshi , Ikeda Tomoaki , Ikenoue Tsuyomu
Published: March 2004

Aim:  To determine whether inflammation and hypoxic‐ischemic insult (HI) act additively to cause brain damage in perinatal animals by examining the dose–response effect of lipopolysaccharide (LPS) administration on HI insult in neonatal rat pups.

Methods:  Seven‐day‐old Wistar rats (n = 119) were divided into three groups: (i) a group that received a pre‐injection of LPS and HI (LPS/HI, 1 mg/kg, n = 31; 0.5 mg/kg, n = 20; 0.1 mg/kg, n = 17); (ii) a group that received a pre‐injection of saline and HI (saline/HI, n = 35); and (iii) those that received LPS alone (1 mg/kg, n = 16). At 4 h after the injection, rat pups from groups (i) and (11) were exposed to unilateral carotid artery ligation, followed by 1 h of hypoxia (8% oxygen in 92% nitrogen) at 33°C. Seven days after the insult, they were sacrificed and their brains removed for histological study. Neuronal damage was categorized as mild, ≤25%; moderate, 25–50%; and severe, ≥50% of surface area on a single section.

Results:  Mortality rate during the experiment was significantly increased in the 1 mg/kg of LPS/HI group (12 of 31, 39%) compared with the saline/HI group (0%). No neuronal damage was observed in the LPS only group. However, when LPS was added to HI, neuronal loss in the cerebral cortex and hippocampus was significantly increased in a dose–response manner.

Conclusion:  LPS potentiates hypoxic‐ischemic insult in a dose‐dependent fashion to cause brain damage in neonatal rats.
Preoperative serum inhibin levels in patients with ovarian tumors
Authors: El‐Shalakany Amr , Abou‐Talib Yasser , Shalaby Hatem Saad , Sallam Maha
Published: March 2004

Aim:  To assess the value of preoperative determination of serum inhibin levels in the prediction of malignancy in women with ovarian tumors. The prediction of malignancy not only helps patient counseling regarding prognosis and extent of surgery but also allows for proper specialist referral.

Methods:  Fifty women with clinically diagnosed ovarian tumors before surgery (patients group) and 32 healthy non‐pregnant women in the early follicular phase of their cycle (controls) were studied. Serum inhibin (total) levels and CA125 were determined using immunoenzymometric assay and enzyme immunoassay, respectively.

Results:  In the patients group, 31 women had malignant ovarian tumors and 19 had benign tumors. Mean (SEM) serum inhibin levels were 0.94 (0.13) U/mL in the control group, 0.91 (0.7) U/mL in women with benign tumors and 1.9 (0.12) U/mL in women with malignant tumors; the differences are statistically significant (P < 0.01). Inhibin levels were significantly higher in women with late‐stage malignant ovarian tumors (III and IV) than in early stages (I and II) and showed no significant difference in relation to menopausal status or the presence of ascites. Taking the 95th centile inhibin level in the control group (1.155 U/mL) as a discriminator level, all women with benign tumors were negative while 67.7% of women with malignant tumors were positive. The inhibin level testing predicted malignancy with a sensitivity of 67.7%, 100% specificity, 100% positive predictive value and 65.52% negative predictive value. Combining CA125 levels (>35 U/mL) with serum inhibin levels (> 1.155 U/mL) improves sensitivity of predicting malignancy to 83.87% and negative predictive value to 75% while maintaining a specificity of 100% and a positive predictive value of 100%. Combining serum inhibin with sonography achieves 96.77% sensitivity and 73.68% specificity for detecting malignancy.

Conclusion:  Preoperative serum inhibin levels in women with ovarian tumors are useful in the prediction of malignancy especially when combined with sonography.
Finite element analysis of notched bar skeletal point stresses and dimension changes due to creep
Authors: WEBSTER G. A. , NIKBIN K. M. , BIGLARI F.
Published: March 2004

In this investigation, finite element calculations have been performed to obtain the creep stress distributions generated in circumferentially notched bar test‐pieces. They have also been made to determine the relation between axial extension and notch throat diameter changes. It has been found that an approximate skeletal point can be identified where the stress state is insensitive to the power law stress dependence of creep. Consistent trends in skeletal point stress ratios to those given in an existing Code of Practice for notch bar creep testing have been obtained. Nevertheless updated values, particularly for sharp notches, are proposed and these have now been inserted into a new version of the Code of Practice. In contrast, the link between extension and notch throat diameter changes has been found to depend on the creep stress index as well as the notch geometry. It is anticipated that the analysis can be used to establish the multi‐axial creep stress deformation and rupture behaviour of materials.
The multiaxial creep ductility of austenitic stainless steels
Authors: SPINDLER M. W.
Published: March 2004

Calculations of creep damage under conditions of strain control are often carried out using either a time fraction approach or a ductility exhaustion approach. In practice, calculations of creep damage are further complicated by the presence of multiaxial states of stress. In the case of the time fraction approach, there are a number of models that can be used to predict the effect of state of stress on creep rupture strength. In particular, Huddleston developed a model from data on stainless steels. The R5 procedure uses a ductility exhaustion approach to calculate creep damage and includes a model for use under triaxial states of stress. The aim of this paper is to describe the development of this model, which is based on considerations of cavity nucleation and growth and was developed from multiaxial creep data on Type 304 and 316 steels.
Fatigue‐creep and plastic collapse of notched bars
Authors: PONTER A. R. S. , CHEN H. , WILLIS M. R. , EVANS W. J.
Published: March 2004

The paper describes a study of the application of a new assessment method, based on the linear matching method (LMM), to the creep fatigue of notched bars of Udimet 720Li at 650 °C. This high strength nickel based alloy is taken as typical of alloys used in high temperature gas turbine applications. The primary purpose of the study is to see whether it is possible to predict the failure modes for such alloys in terms of standard materials data by the evaluation of a sequence of simplified calculations corresponding to the steady state cyclic stress history. These calculations involve the evaluation of limit load, shakedown limit and ratchet limit for perfect plasticity, rapid cycle creep solutions and the evaluation of an elastic follow‐up factor. Within the limitations of the tests, the correlation between predicted failure mode and observed mode is very good and the calculations clearly show up the differences between the two types of notched bars discussed. This implies that LM methods are well suited to the evaluation of failure modes in materials of this type.
Modelling of damage development and failure in notched‐bar multiaxial creep tests
Authors: YATOMI M. , BETTINSON A. D. , O'DOWD N. P. , NIKBIN K. M.
Published: March 2004

Finite‐element predictions of creep rupture in notched specimens are presented in this work. A damage model linked to the creep strain rate and stress triaxiality has been used to predict creep life under multiaxial stress conditions and the predictions have been compared with experimental data for a C–Mn steel. Finite‐element analyses have been conducted using primary–secondary (PS) and primary–secondary–tertiary (PST) creep laws. As expected a PST analysis gives a shorter predicted rupture life than a PS analysis. An additional term was included in the model to allow for an increase in hydrostatic strain due to creep damage. The incorporation of this term improved the agreement between the experimental data and the finite‐element predictions. A further enhancement to the model was to model the initiation and growth of a sharp crack in the vicinity of the notch, through the use of a nodal release technique linked to the damage evolution. It was found that the predictions obtained using the nodal release technique were very similar to those from the PST creep model incorporating the hydrostatic damage term. The effect of mesh size has also been examined and the finite‐element predictions were seen to be quite mesh sensitive with a finer mesh generally giving a shorter predicted life.
Functional and morphological alterations in compound transgenic mice overexpreszing Cu/Zn superoxide dismutaze and amyloid precursor protein
Authors: Harris‐Cerruti Catherine , Kamsler Ariel , Kaplan Batia , Lamb Bruce , Segal Menahem , Groner Yoram
Published: March 2004

Down's syndrome (DS), the phenotypic manifestation of trisomy 21, involves overexpression of chromosome 21‐encoded genes. The gene for amyloid precursor protein (APP), known to be involved in AD pathology, resides on chromosome 21 along with the gene for Cu/Zn superoxide dismutase (SOD1), a key enzyme in the metabolism of oxygen free radicals. We investigated the consequences of a combined increase in APP and SOD1, in a double‐transgenic (tg)‐APP–SOD1 mouse. These mice expressed severe impairment in learning, working and long‐term memory. Expression of long‐term potentiation in hippocampal slices was impaired in both tg‐SOD and tg‐APP–SOD mice, but not in tg‐APP mice, indicating that increased APP by itself did not affect in vitro synaptic plasticity. In tg‐APP–SOD mice, membrane‐bound high molecular weight APP species accumulated while APP cleavage products did not increase and levels of secreted APP were unchanged. Severe morphological damage, including lipofuscin accumulation and mitochondria abnormalities, were found in aged tg‐APP–SOD but not in the other mice. Thus, a combined elevation of the two chromosome 21 genes in tg‐APP–SOD mice induced age‐dependent alterations in morphological and behavioural functions.
Temporally induced Nurr1 can induce a non‐neuronal dopaminergic cell type in embryonic stem cell differentiation
Authors: Sonntag Kai‐Christian , Simantov Rabi , Kim Kwang‐Soo , Isacson Ole
Published: March 2004

The nuclear transcription factor Nurr1 is involved in the development and maintenance of the midbrain dopaminergic (DA) neuronal phenotype. We analysed the cellular and biological effects of Nurr1 during embryonic stem (ES) cell differentiation using the ROSA26‐engineered Tet‐inducible ES cell line J1‐rtTA that does not express transgenes in mature neurons. Induction of Nurr1 at nestin‐positive precursor and later stages of ES cell differentiation produced a non‐neuronal DA cell type including functional DA transporters. In these cells, we found a clear correlation between Nurr1 and TH gene expression and specific midbrain DA cellular markers such as AADC, AHD2 and calbindin. Nurr1 did not alter gene expression of non‐DA neuronal phenotypes and did not influence other midbrain developmental transcription factors, such as Otx1, Otx2, En‐1, GBX2, Pitx3 and lmx1b. In addition, Nurr1 expression was required for maintenance of the DA phenotype and mediated up‐regulation of the tyrosine kinase Ret and associated trophic factor GDNF‐family receptors α 1, 2, and 4. This demonstrates that Nurr1 is sufficient to induce and maintain a midbrain‐like DA biochemical and functional cellular phenotype independent of neurogenesis.
Low‐dose γ‐irradiation promotes survival of injured neurons in the central nervous system via homeostasis‐driven proliferation of T cells
Authors: Kipnis Jonathan , Avidan Hila , Markovich Yifat , Mizrahi Tal , Hauben Ehud , Prigozhina Tatyana B. , Slavin Shimon ,   Michal Schwartz
Published: March 2004

Protective autoimmunity was only recently recognized as a mechanism for attenuating the progression of neurodegeneration. Using a rat model of optic nerve crush or contusive spinal cord injury, and a mouse model of neurodegenerative conditions caused by injection of a toxic dose of intraocular glutamate, we show that a single low dose of whole‐body or lymphoid‐organ γ‐irradiation significantly improved the spontaneous recovery. Animals with severe immune deficiency or deprived of mature T cells were unable to benefit from this treatment, suggesting that the irradiation‐induced neuroprotection is immune mediated. This suggestion received further support from the findings that irradiation was accompanied by an increased incidence of activated T cells in the lymphoid organs and peripheral blood and an increase in mRNA encoding for the pro‐inflammatory cytokines interleukin‐12 and interferon‐γ, and that after irradiation, passive transfer of a subpopulation of suppressive T cells (naturally occurring regulatory CD4+CD25+ T cells) wiped out the irradiation‐induced protection. These results suggest that homeostasis‐driven proliferation of T cells, induced by a single low‐dose irradiation, leads to boosting of T cell‐mediated neuroprotection and can be utilized clinically to fight off neurodegeneration and the threat of other diseases in which defense against toxic self‐compounds is needed.
Neuromodulation of the locomotor network by dopamine in the isolated spinal cord of newborn rat
Authors: Barrière Grégory , Mellen Nicholas , Cazalets Jean‐René
Published: March 2004

We have analysed the action of the neuromodulatory catecholamine, dopamine (DA), on the lumbar locomotor network using an isolated in vitro newborn rat spinal cord preparation. We have also attempted to determine the respective contribution of the D1‐ and D2‐like receptors on the dopamine‐mediated effects. Bath application of DA‐induced slow locomotor‐like rhythmic activity (cycle‐period 20–30 s) in ventral motor roots. Bursts were alternating between segmental right and left side and between ipsilateral flexor and extensor units. This rhythm was blocked by D1 (SCH‐23390) and D2 (raclopride, sulpiride) receptor antagonists, but was unaffected by the dopamine‐β‐hydroxylase blocker, fusaric acid, thereby ruling out indirect noradrenaline‐mediated effects. The D1 agonist, SKF‐81297 induced prolonged slow rhythmic bursting, while the selective D2 agonists, quinpirole and quinelorane, had no effect. DA and the D1 agonist, SKF‐81297 also increased the period and burst amplitude of N‐methyl‐d‐l‐aspartate‐induced locomotor activity. The effects of dopamine and SKF‐81297 on the N‐methyl‐d‐l‐aspartate‐induced rhythm were long‐lasting; persisting for 1 hour after washout. The DA action was blocked by MDL‐12 330 A, an inhibitor of adenylate cyclase, suggesting the involvement of cAMP. Together these results indicate that dopamine can exert neuromodulatory actions on mammalian motor networks via short‐lasting permissive influences and a newly reported, long‐lasting modulation of motor network activity.
Learning and memory performance in mice lacking the GAL‐R1 subtype of galanin receptor
Authors: Wrenn Craige C. , Kinney Jefferson W. , Marriott Lisa K. , Holmes Andrew , Harris Ashley P. , Saavedra Maria C. , Starosta Grzegorz , Innerfield Caitlin E. , Jacoby Arie S. , Shine John , Iismaa Tiina P. , Wenk Gary L. , Crawley Jacqueline N.
Published: March 2004

The neuropeptide galanin induces performance deficits in a wide range of cognitive tasks in rodents. Three G‐protein‐coupled galanin receptor subtypes, designated GAL‐R1, GAL‐R2 and GAL‐R3, have been cloned. The present study examined the role of GAL‐R1 in cognition by testing mice with a null mutation in Galr1 on several different types of learning and memory tasks. Assessments of general health, neurological reflexes, sensory abilities and motor functions were conducted as control measures. Mutant mice were unimpaired in social transmission of food preference and the Morris water maze. In tests of fear conditioning, mutant mice were unimpaired in a delay version of cued fear conditioning. However, mice homozygous for the null mutation were impaired in a trace version of cued fear conditioning. Mutant mice were unimpaired in contextual fear conditioning, whether training was by the delay or trace protocol. General health, neurological reflexes, sensory abilities and motor functions did not differ across genotypes, indicating that the trace fear conditioning deficit was not an artifact of procedural disabilities. The findings of normal performance on several cognitive tasks and a selective deficit in trace cued fear conditioning in homozygous GAL‐R1 mutant mice are discussed in terms of hypothesized roles of the GAL‐R1 subtype. The generally normal phenotype of GAL‐R1 null mutants supports the use of this line for identification of the receptor subtypes that mediate the cognitive deficits produced by exogenous galanin.
Hippocampal neurons in organotypic slice culture are highly resistant to damage by endogenous and exogenous nitric oxide
Authors: Keynes Robert G. , Duport Sophie , Garthwaite John
Published: March 2004

Nitric oxide (NO) has been proposed to mediate neurodegeneration arising from NMDA receptor activity, but the issue remains controversial. The hypothesis was re‐examined using organotypic slice cultures of rat hippocampus, with steps being taken to avoid known artefacts. The NO‐cGMP signalling pathway was well preserved in such cultures. Brief exposure to NMDA resulted in a concentration‐dependent delayed neuronal death that could be nullified by administration of the NMDA antagonist MK801 (10 µm) given postexposure. Two inhibitors of NO synthesis failed to protect the slices, despite fully blocking NMDA‐induced cGMP accumulation. By comparing NMDA‐induced cGMP accumulation with that produced by an NO donor, toxic NMDA concentrations were estimated to produce only physiological NO concentrations (2 nm). In studies of the vulnerability of the slices to exogenous NO, it was found that continuous exposure to up to 4.5 µm NO failed to affect ATP levels (measured after 6 h) or cause damage during 24 h, whereas treatment with the respiratory inhibitors myxothiazol or cyanide caused ATP depletion and complete cell death within 24 h. An NO concentration of 10 µm was required for ATP depletion and cell death, presumably through respiratory inhibition. It is concluded that sustained activity of neuronal NO synthase in intact hippocampal tissue can generate only low nanomolar NO concentrations, which are unlikely to be toxic. At the same time, the tissue is remarkably resistant to exogenous NO at up to 1000‐fold higher concentrations. Together, the results seriously question the proposed role of NO in NMDA receptor‐mediated excitotoxicity.
Asymmetric activation to the context‐dependent right in the right inferior frontal region
Authors: Misaki Masaya , Matsumoto Eriko , Miyauchi Satoru
Published: March 2004

In human spatial recognition, right and left are not recognized symmetrically. Although there have been many studies on the hemispheric asymmetry of the human brain, asymmetries in high‐level recognition (such as independence from input or output hemisphere) have not been studied extensively. We found that the human brain recognizes right and left asymmetrically in high‐level recognition. Experiments were performed in which participants crossed their hands and were required to judge the side of a tactile stimulus on the index finger in two different contexts: ‘which hand was touched’ or ‘on which side of the space the touched hand was located’. The right inferior frontal region was significantly more activated by the ‘contextually defined right’ stimulus (right‐hand stimulation in the ‘which hand’ context and right‐space stimulation in the ‘which space’ context) than by the ‘contextually defined left’ stimulus. However, no activation that was more activated by the ‘contextually defined left’ than by the ‘contextually defined right’ was found. This asymmetric activation suggests that ‘right’ is the more outstanding side for human spatial recognition.
Pharmacological profile of nociceptin/orphanin FQ receptors regulating 5‐hydroxytryptamine release in the mouse neocortex
Authors: Mela Flora , Marti Matteo , Ulazzi Linda , Vaccari Elvis , Zucchini Silvia , Trapella Claudio , Salvadori Severo , Beani Lorenzo , Bianchi Clementina , Morari Michele
Published: March 2004

A synaptosomal preparation was employed to pharmacologically characterize the role of presynaptic nociceptin/orphanin FQ (N/OFQ) receptors (NOP receptors) in the regulation of 5‐hydroxytryptamine release in the Swiss mouse neocortex. In the present study, the NOP receptor ligands N/OFQ, Ac‐RYYRWK‐NH2 and [Phe1ψ(CH2‐NH)Gly2]N/OFQ(1–13)‐NH2 inhibited the K+‐induced [3H]‐5‐HT overflow with similar maximal effects (≈−35%) but different potencies (pEC50 of 8.56, 8.35 and 7.23, respectively). The novel agonist [Arg14,Lys15]N/OFQ also inhibited [3H]‐5‐HT overflow, but the concentration–response curve was biphasic and the efficacy higher (≈−45%). Receptor selectivity of NOP receptor agonists was demonstrated by showing that synaptosomes from NOP receptor knockout mice were unresponsive to N/OFQ, [Arg14,Lys15]N/OFQ and [Phe1ψ(CH2‐NH)Gly2]N/OFQ(1–13)‐NH2 but maintained full responsiveness to endomorphin‐1. Moreover, the inhibitory effect of N/OFQ was prevented by peptide ([Nphe1]N/OFQ(1–13)‐NH2 and UFP‐101) and nonpeptide (J‐113397 and JTC‐801) NOP receptor selective antagonists. Desensitization occurred under perfusion with high (3 and 10 µm) N/OFQ concentrations. This phenomenon was prevented by the protein kinase C inhibitor, bisindolylmaleimide. Moreover, N/OFQ‐induced desensitization did not affect mu opioid receptor responsiveness. Finally, it was observed in a similar preparation of rat cerebrocortical synaptosomes, although it was induced by higher N/OFQ concentrations than that used in the mouse. Together, these findings indicate that presynaptic NOP receptors inhibit 5‐hydroxytryptamine release in the mouse neocortex. Based on present and previous studies, we conclude that NOP receptors in the mouse are subtly different from the homologous receptor population in the rat, strengthening the view that there exist species differences in the pharmacology of central NOP receptors.
Daily body temperature rhythm and heat tolerance in TRPV1 knockout and capsaicin pretreated mice
Authors: Szelényi Z. , Hummel Z. , Szolcsányi J. , Davis J. B.
Published: March 2004

Daily body temperature (DBT) rhythm of mice lacking one of the transient receptor potential (TRP) family of proteins, the capsaicin receptor or TRPV1, was recorded by biotelemetry and found to have significantly higher amplitude than that of wild‐type mice. Capsaicin‐desensitized wild‐mice exhibited an even higher DBT amplitude than did TRPV1 deficient mice. A standard heat load (radiant temperature of 36–37 °C) resulted in similar rises in body core temperature in wild‐type mice and in TRPV1 deficient mice, while capsaicin‐desensitized wild‐type mice exhibited a robust heat‐intolerance. The lack of TRPV1 slightly modifies amplitude of daily body temperature rhythm but does not seem to influence physiological heat defence in mice. In vivo evidence for a TRP protein functioning in the physiological heat‐defence range is still lacking.
Regulation of MAPK/ERK phosphorylation via ionotropic glutamate receptors in cultured rat striatal neurons
Authors: Mao Limin , Tang Qingsong , Samdani Shazia , Liu Zhenguo , Wang John Q.
Published: March 2004

Extracellular signals may regulate mitogen‐activated protein kinase (MAPK) cascades through a receptor‐mediated mechanism. As a signaling superhighway to the nucleus, active Ras‐MAPK cascades phosphorylate transcription factors and facilitate gene expression. In cultured rat striatal neurons, the present work systemically examined the linkage between glutamate receptors and the extracellular signal‐regulated kinase 1/2 (ERK1/2) subclass of MAPK. We found that glutamate induced a rapid and transient phosphorylation of ERK1/2. Similar responses of ERK1/2 phosphorylation were also induced by the ligands selective for each of three subtypes of ionotropic receptors (NMDA, AMPA and kainate), although not by the subgroup‐selective agonists for three subgroups of metabotropic glutamate receptors after 8–9 days in culture. The ERK1/2 phosphorylation induced by all ionotropic receptor agents was dose‐, time‐ and Ca2+ influx‐dependent and occurred in neurons, but not glia. The NMDA‐, AMPA‐ and kainate‐induced ERK1/2 phosphorylation was blocked only by the antagonists selective for respective subtypes. The ERK1/2 phosphorylation induced by these agents was also sensitive to the MAPK kinase 1 (MEK1) inhibitor PD98059 and the MEK1/2 inhibitor U0126. In a further attempt to evaluate the role of active ERK1/2 in activating a downstream transcription factor cAMP response element‐binding protein (CREB), NMDA, AMPA, and kainate were found to increase CREB phosphorylation. The NMDA‐ and AMPA/kainate‐induced CREB phosphorylation was completely and partially blocked by U0126, respectively. These results revealed a positive linkage between ionotropic glutamate receptors and MEK‐sensitive ERK1/2 phosphorylation in striatal neurons. The active ERK1/2 cascade activates the downstream transcription factor CREB to participate in the regulation of gene expression.
Roles of glutamate transporters in shaping excitatory synaptic currents in cerebellar Purkinje cells
Authors: Takayasu Yukihiro , Iino Masae , Ozawa Seiji
Published: March 2004

Several subtypes of glutamate transporters are abundantly expressed near the excitatory synapses on cerebellar Purkinje cells. We investigated the roles of the glutamate transporters in shaping the excitatory postsynaptic currents (EPSCs) and regulating the levels of extracellular glutamate in the mouse cerebellum using a potent blocker of glutamate transporters, dl‐threo‐β‐benzyloxyaspartate (dl‐TBOA). This drug markedly prolonged AMPA receptor‐mediated EPSCs in Purkinje cells evoked by stimulating both parallel fibres and climbing fibres. The decay phase of the prolonged EPSCs was fitted by double exponentials, of which the slower component was preferentially inhibited by a low‐affinity competitive antagonist of AMPA receptors, γ‐d‐glutamyl‐glycine, indicating that the slow component induced by dl‐TBOA was the AMPA receptor‐mediated current activated by lower concentrations of glutamate than those contributing to the peak of the EPSC. This result suggests that dl‐TBOA prolongs the stay of synaptically released glutamate in the synaptic cleft and also induces glutamate spillover to extrasynaptic targets as well as neighbouring synapses. Furthermore, high concentrations of dl‐TBOA in the presence of cyclothiazide generated a continuous inward current in Purkinje cells, of which the amplitude reached the peak level of the climbing‐fibre EPSC. This continuous inward current was abolished by the blocker of AMPA receptors, indicating that the strong inhibition of glutamate uptake causes the rapid accumulation of glutamate in the extracellular space. These results highlight the importance of glutamate transporters in maintaining the proper glutamatergic transmission in Purkinje cell synapses.
Convergence of excitatory and inhibitory inputs onto CCK‐containing basket cells in the CA1 area of the rat hippocampus
Authors: Mátyás Ferenc , Freund Tamás F. , Gulyás Attila I.
Published: March 2004

The number and distribution of excitatory and inhibitory inputs affect the integrative properties of neurons. These parameters have been studied recently for several hippocampal neuron populations. Besides parvalbumin‐ (PV) containing cells that include basket and axo‐axonic cells, cholecystokinin (CCK)‐containing interneurons also form a basket cell population with several properties distinct from PV cells. Here, at the light microscopic level, we reconstructed the entire dendritic tree of CCK‐immunoreactive (IR) basket cells to describe their geometry, the total length and laminar distribution of their dendrites. This was followed by an electron microscopic analysis of serial ultrathin sections immunostained against γ‐aminobutyric acid, to estimate the density of excitatory and inhibitory synapses on their somata, axon initial segments and different subclasses of dendrites. The dendritic tree of CCK‐IR basket cells has an average length of 6300 µm and penetrates all layers. At the electron microscopic level, CCK basket cells receive dendritic inputs with a density of 80–230 per 100 µm. The ratio of inhibitory inputs is relatively high (35%) and increases towards the soma (83%). The total numbers of excitatory and inhibitory synapses converging onto CCK‐IR cells are ∼ 8200. Comparison of the two, neurochemically distinct basket cells reveals that CCK‐containing basket cells receive much less synaptic input than PV cells; however, the relative weight of inhibition is higher on CCK cells. Additional differences in their anatomical and physiological properties predict that CCK basket cells are under a more diverse, elaborate control than PV basket cells, and thus the function of the two populations must be different.
High‐frequency synaptic input contributes to seizure initiation in the low‐[Mg2+] model of epilepsy
Authors: Lasztóczi Bálint , Antal Károly , Nyikos Lajos , Emri Zsuzsa , Kardos Julianna
Published: March 2004

High‐frequency field potential activity between 50 and 400 Hz occurs throughout seizure‐like events recorded from the CA3 region of juvenile rat hippocampal slices under low‐[Mg2+] condition. Another (400–800 Hz) component occurred mainly during preictal paroxysmal spiking and the onsets of seizure‐like events (97%) and less frequently during tonic and clonic phases (38% and 70%, respectively). Short epochs of oscillations in this range were associated with fast negative field potential deflections at the start of field potential transients. Voltage‐clamp recordings from putative CA3 pyramidal cells showed the occurrence of synaptic inputs in the same frequency range at the onset of seizure‐like events and the beginning of preictal or clonic paroxysmal spikes, while the frequency of action potentials never reached that range. The amplitude of fast negative field potential deflection, the rise time of membrane potential or voltage‐clamp current changes and the mean phase coherence were consistent with an increase of synchronization towards the onset of a seizure‐like event. Their parallel changes indicate the involvement of both synaptic and nonsynaptic mechanisms in the synchronization of neuronal activity and the development of seizure‐like events in the low‐[Mg2+] model of epilepsy.
Cloning and expression of short interspersed elements B1 and B2 in ischemic brain
Authors: Kalkkila Juha‐Pekka , Sharp Frank R. , Kärkkäinen Iivari , Reilly Melinda , Lu Aigang , Solway Karen , Murrel Matt , Honkaniemi Jari
Published: March 2004

Global ischemia causes an extensive cell death 3 days after the ischemia in the CA1 region of the hippocampus, which is preceded by induction of a spectrum of genes with both neuroprotective and detrimental properties. This delayed cell death has been suggested to be mainly caused by programmed cell death. Here we applied differential display to characterize transcripts induced by global ischemia after 1 day in Mongolian gerbils, when the cells in the CA1 region are still viable, but initiating the cell death pathway. One of the cloned transcripts turned out to be a repeat sequence termed SINE B2. We also cloned the other member of the SINE family, SINE B1, and found it also to be slightly induced by ischemia in the CA1 region. The SINE repeat regions are not translated and their role in ischemia may be related the neurons' attempt to cope with decreased translational levels and/or genomic reorganization. Together with the previous data demonstrating the inducibility of the SINE transcripts using in vitro stress models, the present study shows that SINE transcripts are stress‐inducible factors in the central nervous system.
Short‐term plasticity visualized with flavoprotein autofluorescence in the somatosensory cortex of anaesthetized rats
Authors: Murakami Hiroatsu , Kamatani Daiki , Hishida Ryuichi , Takao Tetsuro , Kudoh Masaharu , Kawaguchi Tadashi , Tanaka Ryuichi , Shibuki Katsuei
Published: March 2004

In the present study, short‐term plasticity of somatosensory neural responses was investigated using flavoprotein autofluorescence imaging in rats anaesthetized with urethane (1.5 g/kg, i.p.) Somatosensory neural activity was elicited by vibratory skin stimulation (50 Hz for 1 s) applied on the surface of the left plantar hindpaw. Changes in green autofluorescence (λ = 500–550 nm) in blue light (λ = 450–490 nm) were elicited in the right somatosensory cortex. The normalised maximal fluorescence responses (ΔF/F) was 2.0 ± 0.1% (n = 40). After tetanic cortical stimulation (TS), applied at a depth of 1.5–2.0 mm from the cortical surface, the responses elicited by peripheral stimulation were significantly potentiated in both peak amplitude and size of the responsive area (both P < 0.02; Wilcoxon signed rank test). This potentiation was clearly observed in the recording session started 5 min after the cessation of TS, and returned to the control level within 30 min. However, depression of the responses was observed after TS applied at a depth of 0.5 mm. TS‐induced changes in supragranular field potentials in cortical slices showed a similar dependence on the depth of the stimulated sites. When TS was applied on the ipsilateral somatosensory cortex, marked potentiation of the ipsilateral responses and slight potentiation of the contralateral responses to peripheral stimulation were observed after TS, suggesting the involvement of commissural fibers in the changes in the somatosensory brain maps. The present study clearly demonstrates that functional brain imaging using flavoprotein autofluorescence is a useful technique for investigating neural plasticity in vivo.
The developmental dynamics of the brain is reflected by a regionally specific rise and fall of molecular complexity
Authors: Illing Robert‐Benjamin , Jung Christian , Hirschmüller‐Ohmes Ingeborg
Published: March 2004

Tissue samples of inferior colliculus and cerebellar cortex were obtained from rat brains at various postnatal developmental stages. Samples were analysed by two‐dimensional SDS gel electrophoresis. Spots of proteins and their variants were visualized with automated silver staining, the number of spots was determined with a computer‐based image analysis system, and age groups were statistically compared. Judging from the waxing and waning of protein spot numbers, colliculus and cerebellum take distinctly different routes through postnatal development. Whereas molecular complexity in the colliculus was initially high, it decreased soon after the onset of hearing and settled on a significantly lower adult level. By contrast, the cerebellum initially showed low molecular complexity, rose sharply in complexity to reach highest values at late juvenile stages corresponding to peak scores of explorative behaviour, and fell off again to an adult level that remained, however, significantly higher than that of the colliculus. We conclude that the changing diversity of proteins may be used to identify landmarks in brain development.
The actions of monoamines and distribution of noradrenergic and serotoninergic contacts on different subpopulations of commissural interneurons in the cat spinal cord
Authors: Hammar Ingela , Bannatyne B. Anne , Maxwell David J. , Edgley Stephen A. , Jankowska Elzbieta
Published: March 2004

Modulatory actions of monoamines were investigated on spinal commissural interneurons which coordinate left–right hindlimb muscle activity through direct projections to the contralateral motor nuclei. Commissural interneurons located in Rexed lamina VIII, with identified projections to the contralateral gastrocnemius–soleus motor nuclei, were investigated in deeply anaesthetized cats. Most interneurons had dominant input from either the reticular formation or from group II muscle afferents; a small proportion of neurons had input from both. Actions of ionophoretically applied serotonin and noradrenaline were examined on extracellularly recorded spikes evoked monosynaptically by group II muscle afferents or reticulospinal tract fibres. Activation by reticulospinal fibres was facilitated by both serotonin and noradrenaline. Activation by group II afferents was also facilitated by serotonin but was strongly depressed by noradrenaline. To investigate the possible morphological substrates of this differential modulation, seven representative commissural interneurons were labelled intracellularly with tetramethylrhodamine–dextran and neurobiotin. Contacts from noradrenergic and serotoninergic fibres were revealed by immunohistochemistry and analysed with confocal microscopy. There were no major differences in the numbers and distributions of contacts among the interneurons studied. The findings suggest that differences in modulatory actions of monoamines, and subsequent changes in the recruitment of subpopulations of commissural interneurons in various behavioural situations, depend on intrinsic interneuron properties rather than on the patterns of innervation by monoaminergic fibres. The different actions of noradrenaline on different populations of interneurons might permit reconfiguration of the actions of the commissural neurons according to behavioural context.
Calcium‐dependent subthreshold oscillations determine bursting activity induced by N‐methyl‐d‐aspartate in rat subthalamic neurons in vitro
Authors: Zhu Zi‐Tao , Munhall Adam , Shen Ke‐Zhong , Johnson Steven W.
Published: March 2004

We used whole‐cell patch recordings in current clamp to investigate the ionic dependence of burst firing induced by N‐methyl‐d‐aspartate (NMDA) in neurons of the subthalamic nucleus (STN) in slices of rat brain. NMDA (20 µm) converted single‐spike firing to burst firing in 87% of STN neurons tested. NMDA‐induced bursting was blocked by AP5 (50 µm), and was not mimicked by the non‐NMDA receptor agonist AMPA (0.6 µm). Tetrodotoxin (1 µm) converted bursts to oscillations of membrane potential, which were most robust when oscillations ranged between −50 and −70 mV. The NMDA bursts were blocked by an elevated extracellular concentration of Mg2+, but superfusate containing no added Mg2+ either reduced or increased burst firing, depending upon the amount of intracellular current injection. Block of K+ conductances by apamin and tetraethylammonium prolonged burst duration, but iberiotoxin had no effect. NMDA‐induced burst firing and membrane oscillations were completely blocked by superfusate containing no added Ca2+, and they were significantly reduced when patch pipettes contained BAPTA. Selective antagonists for T‐type (mibefradil, 10 µm), L‐type (nifedipine, 3 µm), and N‐type (ω‐conotoxin GVIA, 1 µm) Ca2+ channels had no effect on NMDA burst firing. Superfusate containing a low concentration of Na+ (20 mm) completely abolished NMDA‐induced burst firing. Flufenamic acid (10 µm), which blocks current mediated by Ca2+‐activated nonselective cation channels (ICAN), reversibly abolished NMDA‐depended bursting. These results are consistent with the hypothesis that NMDA‐induced burst firing in STN neurons requires activation of either an ICAN or a Na+–Ca2+ exchanger.
Orexin (hypocretin)/dynorphin neurons control GABAergic inputs to tuberomammillary neurons
Authors: Eriksson Krister S. , Sergeeva Olga A. , Selbach Oliver , Haas Helmut L.
Published: March 2004

High activity of the histaminergic neurons in the tuberomammillary (TM) nucleus increases wakefulness, and their firing rate is highest during waking and lowest during rapid eye movement sleep. The TM neurons receive a prominent innervation from sleep‐active γ‐aminobutyric acidergic (GABAergic) neurons in the ventrolateral preoptic nucleus, which inhibits them during sleep. They also receive an excitatory input from the orexin‐ and dynorphin‐containing neurons in the lateral hypothalamus, which are critically involved in sleep regulation and whose dysfunction causes narcolepsy. We have used intracellular recordings and immunohistochemistry to study if orexin neurons exert control over the GABAergic inputs to TM neurons in rat hypothalamic slices. Dynorphin suppressed GABAergic inputs and thus disinhibits the TM neurons, acting in concert with orexin to increase the excitability of these neurons. In contrast, both orexin‐A and orexin‐B markedly increased the frequency of GABAergic potentials, while co‐application of orexin and dynorphin produced responses similar to dynorphin alone. Thus, orexins excite TM neurons directly and by disinhibition, gated by dynorphin. These data might explain some of the neuropathology of narcolepsy.