bluuebunny/crossref_metadata_2025_split huggingface dataset:
GRP94 (94 kDa glucose‐regulated protein) suppresses ischemic neuronal cell death against ischemia/reperfusion injury
Authors: Bando Yoshio , Katayama Taiichi , Kasai Kousuke , Taniguchi Manabu , Tamatani Michio , Tohyama Masaya 
Published: August 2003

AbstractThe 94 kDa glucose‐regulated protein (GRP94), the endoplasmic reticulum (ER) resident molecular chaperone, has a role in cell death due to endoplasmic reticulum stress (ER stress). Here, we report that expression of GRP94 was increased in human neuroblastoma cells (SH‐SY5Y (SY5Y) cells) exposed to hypoxia/reoxygenation (H/R). H/R mediated death of SY5Y cells was associated with the activation of major cysteine proteases, caspase‐3 and calpain, along with an elevated intracellular calcium concentration. Pretreatment with adenovirus‐mediated antisense GRP94 (AdGRP94AS) led to reduced viability of SY5Y cells after being subjected to H/R compared with wild‐type cells or cells with adenovirus‐mediated overexpression of GRP94 (AdGRP94S). These results indicate that suppression of GRP94 is associated with accelerated apoptosis and that expression of GRP94 (as a stress protein) suppresses oxidative stress‐mediated neuronal death and stabilizes calcium homeostasis in the ER. We also used gerbils with transient forebrain ischemia to study the role of GRP94 in vivo. Neurons with adenovirus‐mediated overexpression of GRP94 were resistant to ischemic damage. These results confirmed that GRP94 could suppress ischemic injury to neurons, suggesting that gene transfer of GRP94 into the brain may have therapeutic potential in the treatment of cerebrovascular disease.
Ca2+‐sensitive regulation of E‐type Ca2+ channel activity depends on an arginine‐rich region in the cytosolic II–III loop
Authors: Leroy Jérôme , Pereverzev Alexey , Vajna Rolf , Qin Ning , Pfitzer Gabriele , Hescheler Jürgen , Malécot Claire O. , Schneider Toni , Klöckner Udo 
Published: August 2003

AbstractCa2+‐dependent regulation of L‐type and P/Q‐type Ca2+ channel activity is an important mechanism to control Ca2+ entry into excitable cells. Here we addressed the question whether the activity of E‐type Ca2+ channels can also be controlled by Ca2+. Switching from Ba2+ to Ca2+ as charge carrier increased within 50 s, the density of currents observed in HEK‐293 cells expressing a human Cav2.3d subunit and slowed down the inactivation kinetics. Furthermore, with Ca2+ as permeant ion, recovery from inactivation was accelerated, compared to the recovery process recorded under conditions where the accumulation of [Ca2+]i was prevented. In a Ba2+ containing bath solution the Ca2+‐dependent changes of E‐type channel activity could be induced by dialysing the cells with 1 µm free [Ca2+]i suggesting that an elevation of [Ca2+]i is responsible for these effects. Deleting 19 amino acids in the intracellular II–III linker (exon 19) as part of an arginine‐rich region, severely impairs the Ca2+ responsiveness of the expressed channels. Interestingly, deletion of an adjacent homologue arginine‐rich region activates channel activity but now independently from [Ca2+]i. As a positive feedback‐regulation of channel activity this novel activation mechanism might determine specific biological functions of E‐type Ca2+ channels.
Rapamycin‐sensitive signalling in long‐term consolidation of auditory cortex‐dependent memory
Authors: Tischmeyer Wolfgang , Schicknick Horst , Kraus Michaela , Seidenbecher Constanze I. , Staak Sabine , Scheich Henning , Gundelfinger Eckart D. 
Published: August 2003

AbstractNew memories initially persist in a labile state and require protein synthesis‐dependent processes of consolidation for long‐term manifestation. Using differential conditioning to linearly frequency‐modulated tones (FMs) we have recently shown that post‐training injections of protein synthesis inhibitors into the auditory cortex of Mongolian gerbils interfere with long‐term memory for a number of days. Here, we have used rapamycin as a pharmacological tool to elucidate signalling pathways that control the synthesis of proteins required for persistent memory storage. In mammalian cells, inhibition of target of rapamycin (TOR)‐mediated pathways was shown to block the translation of distinct classes of mRNAs. Bilateral infusions of rapamycin into the gerbil auditory cortex shortly after FM discrimination training did not impair the maintenance of the newly acquired memory trace for 24 h, but caused profound retention deficits at 48 h after injection. Control experiments showed that the amnesic action is rapamycin‐dependent, confined to the context of memory formation, and suppressed by the antagonist FK506. These data indicate that, in the mammalian brain, activation of rapamycin‐sensitive signalling pathways contributes to long‐term consolidation of a cerebral cortex‐dependent form of memory. Moreover, the finding that rapamycin‐induced amnesia parallels only late effects of conventional protein synthesis inhibitors on FM discrimination memory implies that at least two different protein synthesis‐dependent processes control memory formation. Both are activated during or shortly after learning. Whereas one process is required for the initial maintenance of memory for about one day the second one is involved in the regulation of its long‐lasting persistence in conditioning to FMs.
Endogenous nitric oxide modulates GABAergic transmission to granule cells in adult rat cerebellum
Authors: Wall Mark J. 
Published: August 2003

AbstractNitric oxide (NO) is a gaseous neurotransmitter which plays an important role in neuronal signalling and plasticity throughout the brain. In the cerebellum, NO synthase (NOS) is expressed in parallel fibres and within the internal granule cell layer (IGL). During development there are changes in NOS concentration, distribution and activity within the IGL, suggesting NO may play a role in IGL function. Therefore, the actions of NO in the IGL were investigated. The similar actions of a range of NOS inhibitors and NO scavengers strongly suggested the presence of a tonic level of endogenous NO in the IGL. Both the neuronal and inducible forms of NOS appeared to be sources of this endogenous NO. The effects observed following a reduction in the concentration of endogenous NO were consistent with enhanced granule cell GABAA receptor activation. For example, a reduction in NO concentration led to an increase in the frequency of action potential‐dependent phasic GABAergic inhibitory postsynaptic currents (IPSCs) and produced a TTX‐insensitive GABAA receptor‐mediated current. A direct action of NO on Golgi cell membrane potential and input resistance accounted for the increase in the frequency of phasic GABA release. The mechanism underlying the tonic GABA current is unclear but does not appear to be via the modulation of GABA uptake or the activation of nicotinic acetylcholine receptors. NO is a potentially novel mechanism for tuning GABAergic signalling to granule cells and therefore modulating the throughput of an important cerebellar circuit.
Endocannabinoids contribute to short‐term but not long‐term mGluR‐induced depression in the hippocampus
Authors: Rouach Nathalie , Nicoll Roger A. 
Published: August 2003

AbstractActivation of postsynaptic group 1 metabotropic glutamate receptors (mGluRs) by the agonist DHPG causes a long‐term depression (DHPG‐LTD) of excitatory transmission in the CA1 region of the hippocampus, as well as causing the release of endocannabinoids from pyramidal cells. As cannabinoid agonists cause a presynaptic inhibition at these synapses and DHPG‐LTD is thought to be expressed, at least in part, by a presynaptic mechanism, we examined the possibility that endocannabinoids mediated DHPG‐LTD. We find that antagonists of cannabinoid receptors reduce the acute depression induced by DHPG, but have no effect on the lasting depression. Furthermore, both the acute and the lasting effects of DHPG were unaffected in the CB1 knockout mouse. These findings suggest that endocannabinoids, acting on a non‐CB1 cannabinoid receptor, contribute to the acute depression but not to DHPG‐LTD. Presumably some other retrograde signalling mechanism is responsible for DHPG‐LTD.
Nigral GABAergic inhibition upon cholinergic neurons in the rat pedunculopontine tegmental nucleus
Authors: Saitoh Kazuya , Hattori Satoko , Song Wen‐Jie , Isa Tadashi , Takakusaki Kaoru 
Published: August 2003

AbstractWe investigated, in a midbrain parasagittal slice preparation of Wistar rats (postnatal day 9–17), the synaptic inhibition of neurons in the pedunculopontine tegmental nucleus (PPN), which was mediated by gamma (γ)‐amino‐butyric acid (GABA). Whole‐cell patch‐clamp recording was used, in combination with a single‐cell reverse transcription‐polymerase chain reaction amplification technique, to record synaptic potentials and to identify the phenotype of the recorded PPN neuron. In the presence of the ionotropic glutamate receptor antagonists, 6‐cyano‐2, 3‐dihydroxy‐7‐nitro‐quinoxaline‐2, 3, dione, and dl‐2‐amino‐5‐phosphonovaleric acid, single electrical stimuli were applied to the substantia nigra pars reticulata (SNr), one of the basal ganglia output nuclei. Stimulation of the SNr evoked inhibitory postsynaptic potentials (IPSPs) in 73 of the 104 neurons in the PPN. The IPSPs were abolished with a GABAA receptor antagonist, bicuculline. Inhibitory postsynaptic currents of the neurons were reversed in polarity at approximately −93.5 mV, which was close to the value of the equilibrium potential for chloride ions of −88.4 mV. Single‐cell reverse transcription‐polymerase chain reactions revealed that approximately 30% (9/32) of the PPN neurons that received inhibition from the SNr expressed detectable levels of choline acetyltransferase mRNA. These findings show that output from the SNr regulates the activity of cholinergic PPN neurons through GABAA receptors.
Selective up‐regulation of the growth arrest DNA damage‐inducible gene Gadd45 alpha in sensory and motor neurons after peripheral nerve injury
Authors: Befort Katia , Karchewski Laurie , Lanoue Christopher , Woolf Clifford J. 
Published: August 2003

AbstractThe growth arrest and DNA damage‐inducible gene 45 alpha (Gadd45a) was one of 240 genes found previously by high density oligonucleotide microarray analysis to be regulated in the rat L4 and L5 dorsal root ganglia 3 days after transection of the sciatic nerve (>four‐fold up‐regulation). The Gadd45a mRNA expression profile investigated by northern blot, RNase protection assay and in situ hybridization in the rat shows negligible constitutive mRNA levels in embryonic, neonatal or adult intact dorsal root ganglia. Within 24 h of a sciatic nerve injury, a very large induction is found that persists for as long as regeneration of injured fibres is prevented by peripheral nerve ligation. When axons are allowed to regrow following sciatic nerve crush injury, Gadd45a expression is terminated at later time points, when levels of other markers of injury return towards normal. Colocalization with activating transcription factor 3‐LI and c‐jun mRNA implies that all peripherally injured primary sensory and motor neurons express Gadd45a mRNA. Injury to the central axons of dorsal root ganglion neurons produces only a minimal induction of Gadd45a while peripheral inflammation is without effect. Gadd45a is a specific marker of the presence of peripheral axonal injury in adult primary sensory and motor neurons.
GABA and GABAA receptors at hippocampal mossy fibre synapses
Authors: Bergersen Linda , Ruiz Arnaud , Bjaalie Jan G. , Kullmann Dimitri M. , Gundersen Vidar 
Published: August 2003

AbstractAnatomical and electrophysiological evidence has raised the possibility that corelease of GABA and glutamate occurs at hippocampal mossy fibre synapses which, however, lack the vesicular GABA transporter VGAT. Here, we apply immunogold cytochemistry to show that GABA, like glutamate, has a close spatial relation to synaptic vesicles in rat mossy fibre terminals, implying that a mechanism exists to package GABA in synaptic vesicles. We also show that GABAA and AMPA receptors are colocalized at mossy fibre synapses. The expression of GABA and GABAA receptors is, however, weaker than in inhibitory synapses. Electrical stimuli that recruit mossy fibres evoke monosynaptic GABAA receptor‐mediated signals in post‐synaptic targets that show marked frequency‐dependent facilitation and sensitivity to group II metabotropic receptors, two features that are characteristic of mossy fibre transmission. These results provide further evidence for GABA and glutamate cotransmission at mossy fibre synapses, although paired pre‐ and post‐synaptic recordings will be required to determine the role of GABA at this unusual synapse.
An antagonist of estrogen receptors blocks the induction of adult neurogenesis by insulin‐like growth factor‐I in the dentate gyrus of adult female rat
Authors: Perez‐Martin Margarita , Azcoitia Iñigo , Trejo Jose Luis , Sierra Amanda , Garcia‐Segura Luis M. 
Published: August 2003

AbstractInterdependence between estradiol and insulin‐like growth factor‐I has been documented for different neural events, including neuronal differentiation, synaptic plasticity, neuroendocrine regulation and neuroprotection. In the present study we have assessed whether both factors interact in the regulation of neurogenesis in the adult rat dentate gyrus. Wistar albino female rats were bilaterally ovariectomized and treated with estradiol, insulin‐like growth factor‐I and/or the estrogen receptor antagonist ICI 182,780. Estradiol was administered in a subcutaneous silastic capsule. Insulin‐like growth factor‐I and ICI 182,780 were delivered in the lateral cerebral ventricle. Animals received six daily injections of 5‐bromo‐2‐deoxyuridine and were killed 24 h after the last injection. The total number of 5‐bromo‐2‐deoxyuridine‐positive neurons was significantly increased in animals treated with insulin‐like growth factor‐I, compared with rats treated with vehicles, while rats treated with both insulin‐like growth factor‐I and estradiol showed a higher number of 5‐bromo‐2‐deoxyuridine‐positive neurons than rats treated with insulin‐like growth factor‐I or estradiol alone. The antiestrogen ICI 182,780 blocked the effect of insulin‐like growth factor‐I on the number of 5‐bromo‐2‐deoxyuridine neurons with independence of whether the animals were treated or not with estradiol. These findings suggest that estrogen receptors are involved in the induction of adult neurogenesis by insulin‐like growth factor‐I in the dentate gyrus, and that estradiol and insulin‐like growth factor‐I have a cooperative interaction to promote neurogenesis. The interaction between insulin‐like growth factor‐I and estradiol may participate in changes in the rate of neurogenesis during different endocrine and physiological conditions, and may be related to the decline in neurogenesis with ageing.
Recurrent rectal cancer. The pre‐irradiated primary tumour: can more radiotherapy be given?
Authors: Glimelius B. 
Published: August 2003

AbstractLocal recurrence of rectal cancer after combined radiation and adequate surgery is fortunately rare. It is difficult to manage and most patients have disseminated disease. The treatment possibilities were reviewed based upon a literature search and our own experience. In patients who have already had pre‐ or postoperative radiotherapy to a dose of about 50 Gy over five weeks or 25 Gy in one week, it is possible to re‐irradiate those who develop recurrence up to at least 30 Gy externally over three weeks. In addition, intra‐operative radiotherapy (IORT) or brachytherapy may be given. This strategy may give benefit but cure is not possible unless the recurrence is surgically resectable. There is, however, little information on secondary radiotherapy in these pre‐irradiated patients.
Multi‐modality approach in curative local treatment of early rectal carcinomas
Authors: Hershman M. J. , Myint A. Sun , Makin C. A. 
Published: August 2003

AbstractObjective  Despite recent advances, surgery remains the mainstay for the management of rectal carcinoma. The conventional surgical treatment for low rectal carcinoma is total mesorectal excision. This results in either abdomino‐perineal excision of the rectum (APER) with permanent colostomy or low anterior resection (LAR) usually with a covering stoma. Local resection is an alternative treatment option and this could be offered either using manual trans‐anal resection (TAR) or transanal endoscopic microsurgery (TEM) if the tumour is situated higher.Patients  Patient selection is an important factor if local resection is used. No further treatment is necessary for T1 tumours with clear surgical resection margins. Conventional radical surgery should be offered for T1 tumours with close resection margins (<1 mm) or T2 tumours with higher risk of lymph node metastases. Patients were treated by postoperative chemo‐radiotherapy or radiotherapy, if further radical surgery was not considered appropriate or if the patient refused further surgery. Using this approach, we describe our experience of 100 patients treated from January 1992 to June 2002.Results  Only 13 patients had surgery alone and 87 patients had radiotherapy either pre‐operative (33 patients), postoperative (25 patients) or radical radiotherapy alone (29 patients). Local recurrence occurred in 10% of patients and salvage surgery was offered in over half (6 patients) of these patients. At median follow up of 33 months (range 3–120 months), the overall survival was 77% reflecting the fact that the majority of these patients were elderly with coexisting medical problems. However, cancer specific survival was 96%. More importantly, only 9 patients had colostomies and colostomy‐free survival in our cohort of patients from Liverpool was 91%.Conclusion  We concluded that in selected patients, who were not medically fit (ASA 111 or above) or those who were unable to accept a permanent colostomy, local treatment could be offered with curative intent using a multimodality approach. In our experience, relapses can be salvaged effectively and we recommend a long‐term close follow up policy.
Adjuvant therapy for rectal cancer – the transatlantic view
Authors: Minsky B. D. 
Published: August 2003

AbstractIn North America there are two conventional treatments for clinically resectable rectal cancer. First is surgery and, if the tumour is T3 and/or N1–2, this is followed by postoperative combined modality therapy. The second, for patients with ultrasound T3 or clinical T4 disease, is pre‐operative combined modality therapy followed by surgery and postoperative chemotherapy.Pre‐operative therapy (most commonly combined modality therapy) has gained acceptance as a standard adjuvant therapy. The potential advantages of this approach compared with postoperative therapy include less acute toxicity and enhanced sphincter preservation. Recently completed randomized trials in the US and Germany will provide a definitive answer to this theory. In contrast to the combined modality approach to pre‐operative therapy a number of European centres advocate an intensive short course of radiation (5 Gy × 5 followed one week later by surgery). The only randomized trial which has revealed a significant advantage in survival is the Swedish Rectal Cancer Trial. The Dutch CKVO 95–04 TME trial did not confirm a survival advantage and two metanalyses report conflicting results. Due to selection bias, it is not possible accurately to compare the local recurrence and survival results of intensive short course radiation with conventional pre‐operative combined modality therapy. The intensive short course radiation approach is not used in North America due to its higher toxicity and lack of sphincter preservation. In the Dutch trial the 5‐year local recurrence was 12% with TME and was significantly decreased to 6% with pre‐operative radiation. The 5‐year local recurrence rate in the 324 patients with stage III disease who underwent a TME alone with negative margins was 20%. Therefore, despite TME surgery, radiation therapy is still a necessary component in the adjuvant management of rectal cancer.
Rectal cancer and ulcerative colitis: does it change the therapeutic approach?
Authors: Remzi F. H. , Preen M. 
Published: August 2003

AbstractObjective  The aim of this study was to examine the incidence of coexisting colorectal cancer in ulcerative colitis in a population of patients undergoing ileal pouch anal anastomosis. The frequency of rectal cancer in this population, surgical intervention, general outcomes and cancer recurrence are described.Methods  Data on 1850 patients undergoing restorative proctocolectomy from 1983 to 2001 were reviewed. Information was gathered from data in the department's pelvic pouch database, as well as pathology and surgical reports. Follow‐up questionnaires routinely sent to patients as part of the database were included in the analysis to determine current functional status. Mean follow‐up period was 7.5 years after surgery.Results  Seventy patients had coexisting colorectal cancer at time of IPAA. 7 (10%) of cancers were incidental. Pre‐operative duration of disease was 18.6 years. Twenty‐six of the cancers were rectal cancers. The most common form of anastomosis in the rectal cancers was mucosectomy, especially in pre‐operatively known rectal cancer or low lying dysplasia. Preferred surgical technique for rectal cancer in mucosal ulcerative colitis (UC) included high ligation of mesenteric vessels with radical colectomy and taped occlusion of the rectum with irrigation of the rectal stump with Turnbull solution prior to mucosectomy. Patients with Stage 3 cancers received postoperative chemotherapy. Post‐operative radiation therapy was not commonly recommended. Five of 70 patients were deceased from metastatic colon cancer; 55 patients were confirmed alive with good to excellent pouch function with a follow‐up range of 1–17 years.Conclusion  Restorative proctocolectomy with ileal pouch anal anastomosis is a successful surgical approach for patients with coexisting colorectal cancer in UC. When the appropiate surgical technique is used in patients with colon or rectal cancer, along with adjuvant chemotherapy when appropriate, prognosis and function is very good.