bluuebunny/crossref_metadata_2025 huggingface dataset:
Should NSAID/low‐dose aspirin takers be tested routinely for H. pylori infection and treated if positive? Implications for primary risk of ulcer and ulcer relapse after initial healing
Authors: Hunt R. H. , Bazzoli F.
Published: January 2004

Helicobacter pylori infection and the use of nonsteroidal anti‐inflammatory drugs (NSAIDs) can each result in gastric or duodenal ulcer(s) and ulcer complications. Together, H. pylori infection and NSAIDs account for approximately 90% of peptic ulcer disease. In 2003, the results of studies suggest, and guidelines recommend, the careful selection of anti‐inflammatory drugs – NSAIDs or selective COX‐2 inhibitors (coxibs) based upon patients gastrointestinal history and use of aspirin therapy. Testing for, and cure of, H. pylori infection is recommended in patients prior to the initiation of NSAID therapy and in those who are currently receiving NSAIDs and have a history of dyspepsia, peptic ulcer or ulcer complications. For patients who present with peptic ulcer bleeding but require NSAIDs long‐term, H. pylori eradication therapy should be considered, followed by continuous proton pump inhibitor prophylaxis to prevent re‐bleeding, regardless of which kind of NSAID (nonselective NSAID /coxib) is being prescribed. Routine testing for, and eradication of, H. pylori infection has not been recommended for current takers of NSAIDs with no or low risk of complications. The management of patients taking low‐dose aspirin is complex, but eradication of H. pylori infection alone in those with a past history of bleeding does not guarantee complete protection and therefore a proton pump inhibitor should also be given. The success of eradication therapy should always be confirmed, because of the risk of ulcer recurrence and bleeding in H. pylori‐infected patients who require anti‐inflammatory treatments.
Impact of Helicobacter pylori on society—role for a strategy of ‘search and eradicate’
Authors: Forman D. , Graham D. Y.
Published: January 2004

Helicobacter pylori infection is causally related to gastric cancer, a malignancy associated with high morbidity and poor prognosis, and to peptic ulcer disease, a disease with high morbidity and modest mortality. Theoretically, H. pylori eradication is the most practical means of preventing gastric cancer and peptic ulcer disease. From a public policy perspective, the current evidence is insufficient to assess accurately the magnitude of the benefits of a universal ‘search and treat’ approach. Nonetheless, it is possible to identify high‐risk patients for whom testing for the presence of H. pylori infection, with the intention‐to‐treat infected individuals is currently indicated. This list includes patients with ulcers or dyspepsia, first‐degree relatives of patients with peptic ulcer or gastric cancer, gastric cancer patients after potentially curative resection of their gastric cancer, patients in whom long‐term acid antisecretory therapy or long‐term nonsteroidal anti‐inflammatory drug therapy (including low‐dose aspirin) is planned, and finally those who desire testing. Population screening among asymptomatic individuals with a high risk of gastric cancer, such as Korean‐ and Japanese‐Americans, appears logical, but from a public health perspective should be done as a component of controlled intervention studies. There are no known H. pylori infections without risk of a symptomatic outcome, therefore screening represents a rational strategy for cancer prevention. Adoption of such a policy will require carefully balancing the costs of the programme with its benefits.
Epidemiology and management of gastro‐oesophageal reflux in children
Authors: Gold B. D.
Published: January 2004

The management of gastro‐oesophageal reflux disease (GERD) continues to garner vast amounts of attention among physicians who care for adults. However, there is an increasing awareness of the fact that this disease, as well as several other lifelong digestive diseases (i.e. Crohn's disease) may actually have their origins in childhood. Paediatric gastro‐oesophageal reflux (GER) is likely to share a similar pathophysiology to adult GER, and mounting evidence from published preliminary data suggests a genetic susceptibility to GERD. However, further studies will be necessary to confirm this hypothesis. In children, GER has a distinct presentation from that in adults, with the diagnostic work‐up based upon the patient's age as well as their presenting signs and symptoms. Like their adult counterparts, the early detection and treatment of GER in children may result in a better long‐term outcome, improved quality‐of‐life, and a reduction in overall healthcare burden. While the treatment of GER in infants tends to be conservative (i.e. positioning during feeding, smaller feedings), its management in older children parallels that of adults and includes lifestyle changes and pharmacological therapy. However, with persistent symptoms, acid suppression is the mainstay of GERD management in both children and adults. Several studies in children have verified that acid suppression with a proton pump inhibitor is superior to histamine‐2 receptor antagonists. Among the proton pump inhibitors, both lansoprazole and omeprazole have been the subject of published adult and paediatric studies demonstrating their short and long‐term safety, in addition to their efficacy in a variety of oesophageal and supra‐oesophageal GERD related conditions. These two proton pump inhibitors are manufactured as capsules containing enteric‐coated granules that can be emptied into soft foods or liquids without compromising their pharmacological effects or pharmacokinetic properties. Lansoprazole is also available as a strawberry‐flavoured suspension that is acceptable to children and as an oral disintegrating tablet.
Approaches to endoscopic‐negative reflux disease: part of the GERD spectrum or a unique acid‐related disorder?
Authors: Tack J. , Fass R.
Published: January 2004

Endoscopic‐negative reflux disease (ENRD) is the most common presentation of gastro‐oesophageal reflux disease (GERD)—affecting up to 70% of these individuals. In the last three decades therapeutic studies have focused solely on the treatment of patients with erosive oesophagitis. However, more recent studies have shifted our attention to defining, understanding and treating those with ENRD. GERD has traditionally been approached as a spectrum with ENRD at the mild end and complicated GERD (i.e. patients with erosive oesophagitis, stricture and Barrett's oesophagus) being at the other end, suggesting that patients' disease may progress over time along the spectrum. Current data indicate that ENRD should be approached as a unique entity rather than a part of the GERD spectrum and that over time only a few patients with ENRD will develop GERD‐related complications. Patients with ENRD are a heterogenous group of patients with different aetiologies for their heartburn symptoms, including motor events, reflux of acidic or nonacidic gastric contents, minute changes in intraesophageal pH (pH < 4), mucosal hypersensitivity, and emotional or psychological abnormalities. By dropping the spectrum concept, which emphasizes oesophageal mucosal injury, we can focus our attention on the specific mechanisms that lead to symptom generation in each of the three unique groups of GERD (ENRD, erosive oesophagitis and Barrett's oesophagus) and on the specific therapeutic modalities that benefit each of these individual groups. Acid suppressive therapy with proton pump inhibitors is highly effective in healing erosions and controlling symptoms in those with erosive oesophagitis. In those with ENRD the resolution or control of heartburn with proton pump inhibitor therapy is greater than that with placebo or H2 receptor antagonist, but not as consistent nor as impressive as the results observed in studies of patients with erosive oesophagitis. By considering the mechanisms involved in ENRD symptom generation, future studies that include high‐dose proton pump inhibitors, promotility agents (alone or in combination with proton pump inhibitors), transient lower oesophageal sphincter reducers, or pain modulators (e.g. tricyclic antidepressant agents) may prove beneficial.
Supra‐oesophageal manifestations of gastro‐oesophageal reflux disease
Authors: Malagelada J. R.
Published: January 2004

Supra‐oesophageal manifestations of gastro‐oesophageal reflux disease (GERD) are common and often under‐appreciated, in part due to the absence of classic symptoms of heartburn and regurgitation. Patients with supra‐oesophageal manifestations of GERD may report symptoms involving the pulmonary, otolaryngologic or pharyngeal systems. Endoscopy is often negative and therefore of limited diagnostic value in these patients, and while laryngoscopy and 24 h dual‐channel intra‐oesophageal pH‐metry may have greater yields they are costly, invasive and time‐consuming. Therefore, a trial of proton pump inhibitor therapy is now widely considered a first‐line diagnostic test in those with suspected GERD‐induced supra‐oesophageal symptoms. The dose as well as duration of the proton pump inhibitor trial is dependent upon a patient's presenting symptoms. For example, GERD‐related non‐cardiac chest pain may be relieved with a short‐term (e.g. 1 week) treatment with standard doses of a proton pump inhibitor. The use of high‐dose twice daily proton pump inhibitor therapy for an extended period (e.g. 2–3 months) may be required before any discernible improvement in pulmonary symptoms or pharyngo‐laryngitis is noted. Patients who do not experience symptom improvement following a proton pump inhibitor trial may require further diagnostic evaluations including 24 h oesophageal pH studies, while on acid anti‐secretory therapy, to establish the absence of persistent acid reflux. The role of anti‐reflux surgical or endoscopic interventions in those with supra‐oesophageal manifestations of GERD remains to be established.
Approaches to the long‐term management of adults with GERD—proton pump inhibitor therapy, laparoscopic fundoplication or endoscopic therapy?
Authors: Freston J. W. , Triadafilopoulos G.
Published: January 2004

The goals of gastro‐oesophageal reflux disease (GERD) treatment are to control symptoms, heal the injured oesophageal mucosa, and prevent complications. Pharmacological therapy is effective in producing acute symptom relief and mucosal healing, as well as the long‐term maintenance of remission. Proton pump inhibitors are the mainstay of GERD therapy. However, the need for daily administration, failure to provide complete symptom relief and costs of these agents may limit their use in some patients, prompting a consideration of alternative treatment strategies. Laparoscopic fundoplication may achieve symptom relief and healing of the oesophagitis in these individuals, but its invasiveness, cost and inherent surgical risks have created an interest in endoscopic therapies for GERD, with several emerging during the past few years. These interventions may either be viewed as an alternative therapy or as ‘bridge’ therapy, with patients still choosing to be treated with acid anti‐secretory drugs or fundoplication if the endoscopic procedure fails to provide adequate symptom relief or if symptoms recur. Patient selection is critical for the success of fundoplication as well as endoscopic procedures, with ideal candidates being those with well‐established endoscopically documented GERD, abnormal pH monitoring, normal oesophageal motility studies, and who have experienced at least partial symptom relief with proton pump inhibitor therapy. Hiatal hernia is not a contra‐indication to fundoplication, while endoscopic intervention is best suited for those with a hiatal hernia of less than 3 cm in length. The long‐term efficacy, cost‐effectiveness, and impact of endoscopic procedures on extra‐oesophageal manifestations of GERD and risk for GERD‐related complications has not been determined.
Screening and surveillance of Barrett's oesophagus: what is a cost‐effective framework?
Authors: Spechler S. J. , Barr H.
Published: January 2004

There is a strong association between symptomatic gastro‐oesophageal reflux and oesophageal adenocarcinoma. With this in mind, the American College of Gastroenterology has recently revised its practice guidelines for the screening of patients with chronic gastro‐oesophageal reflux disease (GERD) to identify those at risk of oesophageal adenocarcinoma, and recommends surveillance to identify curable oesophageal neoplasms in patients with established Barrett's oesophagus. Patients  with chronic GERD symptoms, particularly those aged over 50 years, should undergo upper endoscopy. Patients  found to have Barrett's oesophagus should be treated with acid suppression for GERD symptoms and then undergo regular surveillance endoscopy. Surveillance endoscopy every 3 years is recommended for those without dysplasia. For patients with verified low‐grade dysplasia, yearly surveillance endoscopy is recommended. For those with focal high‐grade dysplasia (defined as high‐grade dysplastic changes involving fewer than five crypts), the condition may be followed with endoscopic surveillance performed at 3‐month intervals. If there is verified, multifocal high‐grade dysplasia, intervention (e.g. oesophagectomy) may be considered. Both observational and computer models suggest a benefit associated with screening and surveillance. Endoscopic screening and surveillance for Barrett's oesophagus compares favourably with mammography for the detection of breast cancer and other accepted medical practices.
Approaches to Barrett's oesophagus treatment—the role of proton pump inhibitors and other interventions
Authors: Jankowski J. , Sharma P.
Published: January 2004

Despite implementation of screening and surveillance strategies, a significantly large number of patients with Barrett's oesophagus remain undiagnosed. In those who are identified, the management options include acid reduction therapies with proton pump inhibitors or anti‐reflux surgery. Endoscopic ablative therapies have also been attempted. In addition to having inherent procedure‐related risks with ablative therapies, these alternatives may be limited by high rates of failure, need for continued acid suppressive therapy, metaplasia persistence under otherwise normal appearing tissue, need for procedural expertise, and continued risk for adenocarcinoma development. Therefore, a widely applicable chemoprevention strategy that cost‐effectively reduces the rate of progression from oesophagitis to adenocarcinoma in high‐risk patients and perhaps those at lower rates of risk is highly desirable. The AspECT trial currently underway is seeking to determine the effects of high‐ and low‐dose proton pump inhibitor therapy with and without low‐dose aspirin as Barrett's oesophagus chemoprevention.
Appropriate use of proton pump inhibitors with traditional nonsteroidal anti‐inflammatory drugs and COX‐2 selective inhibitors
Authors: Kimmey M. B. , Lanas A.
Published: January 2004

Nonsteroidal anti‐inflammatory drugs (NSAIDs) are one of the most commonly used classes of medications in the USA, annually accounting for over 100 million prescriptions. Gastrointestinal complications associated with NSAIDs are common, and result in a substantial amount of morbidity and mortality, despite the advent of the cyclooxygenase‐2 selective inhibitors or ‘coxibs’. Emerging clinical and economic data suggest that, depending on the baseline risk to patients, the use of a traditional NSAID alone or in combination with a proton pump inhibitor are effective and well tolerated alternatives to coxibs. The optimal therapeutic strategy for NSAID selection and use of co‐therapy should be guided by a consideration of each patient's risk of having an adverse event arising from the NSAID. Patients at the highest risk for gastrointestinal complications with traditional NSAIDs are those with a history of an ulcer or ulcer complication, those of advanced age (greater than 65 years), and those receiving concurrent aspirin, anticoagulants or corticosteroid therapy. Proton pump inhibitor co‐therapy is highly effective in reducing NSAID‐related dyspeptic symptoms, healing the injured mucosa even in those who continue to ingest NSAIDs, and preventing gastrointestinal complications. In addition to their selective use in patients who experience NSAID‐related dyspepsia and other symptoms, proton pump inhibitor co‐therapy should be considered in those at high risk (with coxib or traditional NSAID therapy) and is necessary in high‐risk patients receiving aspirin, with or without NSAID therapy.
Management of peptic ulcer bleeding—the roles of proton pump inhibitors and Helicobacter pylori eradication
Authors: Holtmann G. , Howden C. W.
Published: January 2004

Peptic ulcer bleeding is associated with substantial morbidity and mortality. The goals of management are to control any active bleeding and prevent re‐bleeding and then to heal the ulcer and prevent its recurrence. Initial management strategies are guided by the patient's clinical condition and endoscopic findings. Thus, treatment may consist of endoscopic and medical therapy and, sometimes, surgery. Control of acid secretion, preferably with proton pump inhibitor therapy in the initial management continues to evolve; it has also been used as both an adjunct to endoscopic therapy and as primary treatment. These agents have been found to be effective in some trials in the reduction of re‐bleeding and the need for surgery, although there is no clear benefit demonstrated for overall mortality. Proton pump inhibitors have been administered either intravenously or orally in different trials. The long‐term management of patients with peptic ulcer, after the initial bleeding episode, should include patient stratification based upon risk factors for ulcer recurrence (i.e. Helicobacter pylori infection, use of aspirin or nonsteroidal anti‐inflammatory drugs). Elimination or modification of these risk factors reduces the risk of ulcer recurrence and, hence, of recurrent ulcer bleeding.
Balancing the ideal versus the practical—considerations of colorectal cancer prevention and screening
Authors: Lieberman D. A. , Atkin W.
Published: January 2004

Colorectal cancer is responsible for over 500 000 deaths annually world‐wide. Death from colorectal cancer is preventable, primarily through early diagnosis of disease that has not metastasized. The disease itself may be prevented by the detection and removal of colorectal adenomas, from which more than 95% of colorectal cancers arise. Currently there are several screening methods for the disease. These include faecal occult blood tests, sigmoidoscopy, barium enema and colonscopy as well as emerging methods of virtual colonoscopy and faecal DNA testing. While direct and indirect evidence support the efficacy of these tests they differ from each other in their sensitivity, specificity, cost, and safety. Various professional organizations in different geographical regions of the world have published recommendations on which screening methods to use and when in patients at average‐ or high‐risk. The challenge in reducing the incidence and mortality of this disease lies in increasing accessibility to and compliance with screening and delivery within a quality assured programme.
Disruption of self‐organized actions in monkeys with progressive MPTP‐induced parkinsonism. I. Effects of task complexity
Authors: Pessiglione Mathias , Guehl Dominique , Hirsch Etienne C. , Féger Jean , Tremblay Léon
Published: January 2004

Parkinson's disease (PD) is characterized by motor symptoms, usually accompanied by cognitive deficits. The question addressed in this study is whether complexity of routine actions can exacerbate parkinsonian disorders that are often considered to be motor symptoms. To examine this question, we trained four vervet monkeys (Cercopithecus aethiops) to perform three multiple‐choice retrieval tasks. In order of ascending complexity, rewards were freely available (task 1), covered with transparent sliding plaques (task 2), and covered with opaque sliding plaques cued by symbols (task 3). Thus, from task 1 to task 2 we added a motor difficulty – the recall of context‐adapted movement; and from task 2 to task 3 we added a cognitive difficulty: the recall of symbol–reward associations. The more complex the task, the longer it took to learn, but after extensive training the performance was stable in all tasks, with similar retrieval durations. The monkeys then received systemic 1‐methyl‐4‐phenyl‐1,2,3,6‐tetrahydropyridine (MPTP) injections (0.3–0.4 mg/kg) every 4–7 days, until the first motor symptoms appeared. In the course of MPTP intoxication, the behavioural performance declined while the motor symptoms were absent or mild – the retrieval duration increased, and non‐initiated choices and hesitations between choices became frequent. Interestingly, this decline was in proportion to task complexity, and was particularly pronounced with the cognitive difficulty. Furthermore, freezing appeared only with the cognitive difficulty. We therefore suggest that everyday cognitive difficulties may exacerbate hypokinesia (lack of initiation, abnormal slowness) and executive disorders (hesitations, freezing) in the early stages of human PD.
Modulation of feeding behaviour by blocking purinergic receptors in the rat nucleus accumbens: a combined microdialysis, electroencephalographic and behavioural study
Authors: Kittner H. , Krügel U. , Hoffmann E. , Illes P.
Published: January 2004

The nonspecific P2 receptor antagonist pyridoxalphosphate‐6‐azophenyl‐2′,4′‐disulphonic acid (PPADS), the nonspecific P1 receptor antagonist 8‐(p‐sulphophenyl)‐theophylline (8‐SPT) and the combination of both were applied by retrograde microdialysis into the nucleus accumbens (NAc) before and during feeding of 18‐h food‐deprived rats. In addition to the registration of behavioural parameters, such as the amount and duration of food intake, the feeding‐induced changes in dopamine (DA) concentration and the concomitant changes of neuronal activity in the NAc and the ventral tegmental area (VTA) were simultaneously determined. The perfusion with PPADS (20 µm) diminished the amount of food intake and the duration of feeding. Furthermore, the P2 receptor antagonist blocked the feeding‐induced DA release and prevented the feeding‐elicited changes of the electroencephalography (EEG) power distribution which was characterised by an increase in the power of the 8.0–13.0‐Hz frequency band in the NAc and the VTA. The effects of PPADS could be completely prevented by the concomitantly perfused adenosine receptor antagonist 8‐SPT (100 µm). When given alone, 8‐SPT increased the amount of food ingested, the duration of feeding and the EEG power of the higher frequency range, particularly between 19.0 and 30.0 Hz, in both the NAc and the VTA. The feeding‐elicited DA release was supplemented to the enhanced DA level caused by the perfusion with 8‐SPT in an additive manner. The P2 and P1 receptor antagonists interact antagonistically in the modulation of feeding behaviour and the feeding‐induced changes of EEG activity suggesting that both endogenous extracellular ATP and adenosine are involved in the regulation of the feeding‐associated mesolimbic neuronal activity in a functionally antagonistic manner.
The antiepileptic drug levetiracetam selectively modifies kindling‐induced alterations in gene expression in the temporal lobe of rats
Authors: Gu Jessie , Lynch Berkley A. , Anderson Dina , Klitgaard Henrik , Lu Sun , Elashoff Michael , Ebert Ulrich , Potschka Heidrun , Löscher Wolfgang
Published: January 2004

Gene expression profiling by microarrays is a powerful tool for identification of genes that may encode key proteins involved in molecular mechanisms underlying epileptogenesis. Using the Affymetrix oligonucleotide microarray, we have surveyed the expression levels of more than 26,000 genes and expressed sequence tags (ESTs) in the amygdala‐kindling model of temporal lobe epilepsy. Furthermore, the effect of the antiepileptic drug levetiracetam (LEV) on kindling‐induced alterations of gene expression was studied. Treatment of rats with LEV during kindling acquisition significantly suppressed kindling development. For gene expression profiling, six groups of rats were included in the present study: (i) and (ii) sham‐operated rats treated with saline or LEV; (iii) and (iv) electrode‐implanted but non‐kindled rats treated with saline or LEV; (v) and (vi) kindled rats treated with saline or LEV. Treatment was terminated after 11 or 12 daily amygdala stimulations, when all vehicle‐treated rats had reached kindling criterion, i.e. a stage 5 seizure. Twenty‐four hours later, the ipsilateral temporal lobe was dissected for mRNA preparation. Six temporal lobe preparations from each group were analysed for differential gene expression. In control (non‐kindled) rats, LEV treatment was devoid of any significant effect on gene expression. In saline‐treated kindled rats, a large number of genes were observed to display mRNA expression alterations compared with non‐kindled rats. LEV treatment induced marked effects on gene expression from kindled rats. Previously described epilepsy‐related genes, such as neuropeptide Y (NPY), thyrotropin‐releasing hormone (TRH) and glial fibrillary acidic protein (GFAP) were confirmed to be up‐regulated by kindling and partially normalized by LEV treatment. Real‐time quantitative polymerase chain reaction confirmed NPY, TRH and GFAP expression data from chip experiments. Furthermore, a number of novel genes were identified from the gene chip experiments. A subgroup of these genes demonstrated correlation between expression changes and kindled phenotype measurements. In summary, this study identified many genes with potentially important roles in epileptogenesis and highlighted several important issues in using the gene chip technology for the study of animal models of CNS disorders.
CNTF promotes survival of retinal ganglion cells after induction of ocular hypertension in rats: the possible involvement of STAT3 pathway
Authors: Ji Jian‐Zhong , Elyaman Wassim , Yip Henry K. , Lee Vincent W. H. , Yick Leung‐Wah , Hugon Jacques , So Kwok‐Fai
Published: January 2004

We examined the neuroprotective effect of ciliary neurotrophic factor (CNTF) on retinal ganglion cells (RGCs) in a rat glaucoma model with increased intraocular pressure (IOP) and studied the CNTF‐mediated activation of Janus kinase/signal transducer and activator of transcription (JAK‐STAT) pathway. Elevated IOP was induced by laser photocoagulation of the episcleral and limbal veins. The survival of RGCs was studied using Fluoro‐Gold labelled in ocular hypertensive eyes with or without CNTF intravitreal injection. Immunochemical staining and immunoblot analysis for CNTF and phosphorylated STAT3 (pSTAT3) were performed. There was a significant and progressive loss of RGCs in the retinas following the induction of elevated IOP. A single intravitreal injection of 2 µg in 2 µL CNTF significantly protected RGCs up to 4 weeks. pSTAT3 was only transiently expressed in ocular hypertensive eyes. However, in eyes treated with CNTF, pSTAT3 was observed up to 2 weeks after the induction of elevated IOP. In ocular hypertensive eyes, CNTF‐positive cells were found in the inner nuclear layer (INL), and there was a transient increase in the pSTAT3 cells in the ganglion cell layer and INL. Immunoblots showed that STAT3 was transiently phosphorylated after IOP increase, but with an injection of CNTF, pSTAT3 protein was observed up to 2 weeks after hypertensive glaucoma induction. Laser‐induced chronic ocular hypertension in rats resulted in the death of RGCs and a transient activation of STAT3 in the retina. Intravitreal injection of CNTF showed a significant protection of RGCs, and the JAK‐STAT signalling could be one of the important pathways that underlie the mechanism of CNTF neuroprotection in this rat glaucoma model.
Suppressing calcium/calmodulin‐dependent protein kinase II activity in the ventral tegmental area enhances the acute behavioural response to cocaine but attenuates the initiation of cocaine‐induced behavioural sensitization in rats
Authors: Licata Stephanie C. , Schmidt Heath D. , Pierce R. Christopher
Published: January 2004

In the present experiments we administered an α‐amino‐3‐hydroxy‐5‐methyl‐4‐isoxazole propionic acid (AMPA) receptor antagonist (CNQX), N‐methyl‐D‐aspartate (NMDA) receptor antagonist (AP‐5), or l‐type calcium channel blocker (diltiazem) directly into the ventral tegmental area (VTA) before each of four daily systemic cocaine injections in order to assess their influence on the initiation phase of behavioural sensitization. Results indicated that pretreatment with CNQX or AP‐5 impaired the initiation of cocaine‐induced behavioural sensitization. Intra‐VTA administration of diltiazem significantly increased the behavioural activation induced by an acute cocaine injection, but impaired the development of cocaine‐induced behavioural sensitization. Because AMPA and NMDA receptors, as well as l‐type calcium channels are calcium permeable, we also investigated the role of the calcium‐activated second messenger calcium/calmodulin‐dependent protein kinase II (CaM‐KII). Similar to the results obtained with diltiazem, administration of the CaM‐KII inhibitor KN‐93 into the VTA enhanced the acute behavioural response to cocaine but prevented the augmentation of cocaine‐induced behavioural hyperactivity following repeated injections. Consistent with this finding, the behavioural hyperactivity produced by cocaine was markedly enhanced among homozygous α‐CaM‐KII knockout mice but the initiation of behavioural sensitization to cocaine was attenuated relative to wild‐type mice. Separate experiments performed in rats demonstrated an increase in total protein levels of CaM‐KII in the VTA 24 h after the last of seven daily injections of cocaine. Taken together, these results indicate that blocking l‐type calcium channels or impairing CaM‐KII activity in the VTA augments the acute behavioural hyperactivity induced by cocaine. The present findings also suggest that increased calcium influx through AMPA receptors, NMDA receptors and l‐type calcium channels on dopaminergic neurons in the VTA contributes significantly to the initiation of behavioural sensitization by amplifying calcium signalling through CaM‐KII.
Stimulus locking and feature selectivity prevail in complementary frequency ranges of V1 local field potentials
Authors: Kayser Christoph , König Peter
Published: January 2004

The local field potential (LFP) is a population measure of neuronal activity complementary to spike trains. Whereas the response properties of the spiking activity in the visual cortex have been characterized extensively, the responses of the LFP have not been well explored. No coherent picture exists about which frequency ranges exhibit feature tuning or show stimulus locked activity. Addressing this, we recorded LFP in the primary visual cortex of alert cats and calculated the tuning indices for orientation, spatial and temporal frequency. Furthermore, we quantified the locking of the power in different LFP frequency bands to the velocity profile of artificial and natural stimuli. We found that the LFP in alert animals is well tuned with similar specificity to orientation, spatial frequency and temporal frequency. Tuning to these features is most prominent in two frequency bands (8–23 Hz and 39–109 Hz). In two complementary frequency bands (23–39 Hz and above 109 Hz) the dynamics of the LFP power is locked tightly to the temporal structure of the stimulus. This locking is furthermore independent of the spatial structure of the stimulus. Together these four frequency bands cover the whole frequency range investigated. In contrast to previous studies, which often reported correlates of visual processing only in a limited frequency range of the LFP, the present results suggest that the entire frequency range of the LFP can be assigned a role in visual processing.
Median raphe mediates estrogenic effects to the hippocampus in female rats
Authors: Prange‐Kiel Janine , Rune Gabriele M. , Leranth Csaba
Published: January 2004

Subcortical regions such as the medial septum–diagonal band of Broca and supramammillary area have been shown to mediate indirect oestrogenic effects on hippocampal morphology and function. Here, the role of the median raphe (MR), a serotonergic subcortical structure, is studied. To this end, 17β‐estradiol‐filled 30‐gauge cannulae were implanted into the MR of female ovariectomized rats; cholesterol‐filled cannulae served as controls. After seven days, using unbiased electron microscopic stereological calculations and semiquantitative analysis, the spine synapse density and surface density of glial fibrillary acidic protein‐positive astrocyte processes, respectively, were determined in the stratum radiatum of the CA1 region of the hippocampus. Changes in the serotonergic innervation of the hippocampal CA1 region were determined by immunohistochemistry and subsequent morphometric analysis. In the stratum radiatum of the CA1 region, local estradiol application into the MR resulted in a 47% increase in spine synapse density. Simultaneously, the density of glial fibrillary acidic protein‐positive fibers decreased by 16%. The density of serotonin (5‐HT) innervation of the strata lacunosum moleculare and radiatum of the CA1 region of the hippocampus was reduced in response to estradiol, as shown by a decrease in the length of fibers (27.6 and 48.3% decrease, respectively) and the number of large varicosities (32.5 and 38.8% decrease, respectively). These observations suggest a major role of the MR in mediating oestrogenic effects on the hippocampus and an involvement of the serotonergic system.
Turning behaviour induced by stimulation of the 5‐HT receptors in the subthalamic nucleus
Authors: Belforte J. E. , Pazo J. H.
Published: January 2004

The basal ganglia, which receive a rich serotonergic innervation, have been implicated in hyperkinetic and hypokinetic disorders. Moreover, a decrease in subthalamic nucleus (STN) activity has been associated with motor hyperactivity. To address the role of subthalamic serotonergic innervation in its motor function, turning behaviour was studied in rats with stimulation of the subthalamic serotonin (5‐HT) receptors by intracerebral microinjections. The intrasubthalamic administration of 5‐HT induced dose‐dependent contralateral turning behaviour, with a maximal effect at a dose of 2.5 µg in 0.2 µL. Similar results were observed with microinjections of other 5‐HT receptor agonists: quipazine (a 5‐HT2B/C/3 agonist), MK‐212 (a 5‐HT2B/C agonist) and m‐chlorophenylbiguanidine (a 5‐HT3 agonist), while microinjections of 5‐HT into the zona incerta or in the previously lesioned STN were ineffective. The effect of 5‐HT was blocked by coadministration of the antagonist mianserin. Stimulation of subthalamic 5‐HT receptors in animals bearing a lesion of the nigrostriatal pathway did not modify the motor response, which indicates that the dopamine innervation of the nucleus is not involved in this effect. Kainic acid lesion of the substantia nigra pars reticulata (SNr) suppressed the contralateral rotations elicited by stimulation of 5‐HT2B/C/3 subthalamic receptors. This suggests a role of the subthalamic–nigral pathway in the turning activity. Furthermore, the partial blockade of glutamatergic receptors in the SNr by the antagonist DNQX increased the contralateral circling elicited by stimulation of 5‐HT receptors in the STN. We concluded that the activation of the 5‐HT2B/C and 5‐HT3 subthalamic receptors elicited contralateral turning behaviour, probably via the subthalamic–nigral pathway.
Reticular stimulation evokes suppression of CA1 synaptic responses and generation of theta through separate mechanisms
Authors: Jiang Fengli , Khanna Sanjay
Published: January 2004

The induction of hippocampal theta by reticular stimulation involves a relay to the hippocampus via the posterior hypothalamic–supramammillary region and then the medial septum. Interestingly, sensory‐ or behaviour‐induced theta is accompanied by suppression of hippocampal field CA1 synaptic responses. In the present study, performed on anaesthetized rats, we observed that reticular stimulation also induced a suppression of the CA1 pyramidal cell population spike and the corresponding dendritic field excitatory postsynaptic potential evoked by field CA3 stimulation. This suppression was observed at stimulation intensity below the threshold for generation of CA1 theta and was maximal at stimulation intensities at the threshold for theta. The frequency and amplitude of theta waves, by contrast, increased further with increasing reticular stimulation voltage. Neural inactivation by microinjection of the local anaesthetic procaine (20% w/v, 0.1–0.2 µL) or the inhibitory ligand gamma aminobutyric acid (0.8 m, 0.5 µL) in the posterior hypothalamic regions, especially the ipsilateral medial supramammillary region, or the medial septum attenuated both the suppression of CA1 pyramidal cell synaptic excitability and theta generation. However, the effects of microinjection on suppression and theta were not always in parallel. Furthermore, the effect of microinjection of gamma aminobutyric acid on reticularly elicited suppression was observed from relatively fewer sites in the posterior hypothalamus as compared with that on theta activation. These results suggest that reticular stimulation evokes an inhibition of CA1 pyramidal cell excitability that (i) is mediated, at least in part, via medial supramammillary and septal regions, but (ii) involves a separate neural pathway from theta generation.
Properties of delay‐period neuronal activity in the primate prefrontal cortex during memory‐ and sensory‐guided saccade tasks
Authors: Tsujimoto Satoshi , Sawaguchi Toshiyuki
Published: January 2004

The dorsolateral prefrontal cortex (DLPFC) is involved in visuospatial short‐term (or working) memory. Its cellular basis has been widely examined using the delayed‐response paradigm in nonhuman primates. Sustained delay‐period activity in DLPFC neurons with directional difference (i.e. directional delay‐period activity) has been thought to represent visuospatial short‐term (or working) memory. However, little is known about the activity of these neurons during a delay period when the sensory input remains. To address this issue, we examined neuronal activity in the DLPFC while macaque monkeys performed a memory‐guided saccade (MGS) task and a delayed visually guided saccade (VGS) task. The MGS task required a memory‐guided saccade for a remembered target location. The VGS task had the same temporal sequence as the MGS task, but the sensory stimulus remained during the delay period. We found that most of the DLPFC neurons with directional delay‐period activity showed sustained activation during the ‘delay’ period in the VGS task only (‘V‐neurons’, 49%), or in both tasks (‘MV‐neurons’, 46%). Neurons showing directional delay‐period activity in the MGS task only (‘M‐neurons’) were only 5% of the DLPFC neurons with directional delay‐period activity. These findings indicate that most DLPFC neurons that are active during the delay period are also active when the sensory stimulus remains, suggesting that DLPFC neurons driven by mnemonic information are also driven by sensory input. Such sustained representation of information should have potential utility in flexible cognitive controls of behaviour.
The serum‐ and glucocorticoid‐induced kinase SGK inhibits mutant huntingtin‐induced toxicity by phosphorylating serine 421 of huntingtin
Authors: Rangone Hélène , Poizat Ghislaine , Troncoso Juan , Ross Christopher A. , MacDonald Marcy E. , Saudou Frédéric , Humbert Sandrine
Published: January 2004

Huntington's disease (HD) is caused by abnormal polyglutamine (polyQ) expansion in the protein huntingtin. We have previously demonstrated the importance of the insulin‐like growth factor I (IGF‐1)/Akt pathway in HD. Indeed, upon IGF‐1 activation, Akt phosphorylates polyQ‐huntingtin at serine 421 and abrogates its toxicity. In addition, we have demonstrated that Akt is altered in the brain of HD patients. Here, we investigate the role of the serum‐ and glucocorticoid‐induced kinase (SGK) in HD. We show that SGK phosphorylates huntingtin at serine 421 and that phosphorylation can protect striatal neurons against polyQ‐huntingtin‐induced toxicity. We find that SGK levels are increased in the brain of HD patients. Using a cellular model of HD, we demonstrate that the SGK dysregulation induced by polyQ‐huntingtin occurs via the p38/MAPK pathway. Collectively, our results strongly suggest the involvement of SGK in HD and further imply that IGF‐1 downstream signalling is a key transduction pathway that regulates the toxicity of huntingtin.
Kv1 currents mediate a gradient of principal neuron excitability across the tonotopic axis in the rat lateral superior olive
Authors: Barnes‐Davies Margaret , Barker Matthew C. , Osmani Fatima , Forsythe Ian D.
Published: January 2004

Principal neurons of the lateral superior olive (LSO) detect interaural intensity differences by integration of excitatory projections from ipsilateral bushy cells and inhibitory inputs from the medial nucleus of the trapezoid body. The intrinsic membrane currents active around firing threshold will form an important component of this binaural computation. Whole cell patch recording in an in vitro brain slice preparation was employed to study conductances regulating action potential (AP) firing in principal neurons. Current‐clamp recordings from different neurons showed two types of firing pattern on depolarization, one group fired only a single initial AP and had low input resistance while the second group fired multiple APs and had a high input resistance. Under voltage‐clamp, single‐spiking neurons showed significantly higher levels of a dendrotoxin‐sensitive, low threshold potassium current (ILT). Block of ILT by dendrotoxin‐I allowed single‐spiking cells to fire multiple APs and indicated that this current was mediated by Kv1 channels. Both neuronal types were morphologically similar and possessed similar amounts of the hyperpolarization‐activated nonspecific cation conductance (Ih). However, single‐spiking cells predominated in the lateral limb of the LSO (receiving low frequency sound inputs) while multiple‐firing cells dominated the medial limb. This functional gradient was mirrored by a medio‐lateral distribution of Kv1.1 immunolabelling. We conclude that Kv1 channels underlie the gradient of LSO principal neuron firing properties. The properties of single‐spiking neurons would render them particularly suited to preserving timing information.
Pyruvate limits zinc‐induced rat oligodendrocyte progenitor cell death
Authors: Kelland Eve E. , Kelly Mary D. , Toms Nick J.
Published: January 2004

A growing body of evidence suggests that excessive Zn2+ release plays a key role in inducing neuronal death during central nervous system injury. However, the possible cytotoxicity of extracellular Zn2+ to oligodendrocyte lineage cells remains unknown. Employing cultures of rat oligodendrocyte progenitor cells (OPC), we report here that OPC are vulnerable to increased extracellular Zn2+ levels and that pyruvate limits Zn2+‐induced OPC death. Zn2+‐induced concentration‐dependent (pEC50 = −4.1 ± 0.1) OPC death, which was insensitive to both α‐amino‐3‐hydroxy‐5‐methyl‐4‐isoxazolepropionic acid receptor (Evans Blue) and l‐type Ca2+ channel (nicardipine) inhibition. Neither kainate nor nicardipine influenced OPC 65Zn2+ accumulation, in contrast with the Zn2+ ionophore, pyrithione. Cytotoxic extracellular Zn2+ concentrations failed to increase OPC reactive oxygen species production and the antioxidant reagents, trolox, N,N′‐diphenyl‐1,4‐phenylenediamine and N‐tert‐butyl‐α‐phenylnitrone did not afford significant protection from Zn2+ insults. The apoptotic inducer staurosporine induced the appearance of known apoptotic markers [pyknotic nuclei and caspase‐3 specific (120 kDa) α‐fodrin cleavage fragment], events not reproduced with Zn2+ insults. Zn2+ insults were also insensitive to the pan‐caspase inhibitor Z‐VAD‐fmk. However, pyruvate afforded significant OPC protection from lethal Zn2+ insults. We conclude that cultured OPC are vulnerable to Zn2+ insults, via a nonoxidative stress and noncaspase‐3‐based mechanism, involving Zn2+ inhibition of OPC glycolysis.
Enhanced generation of intracellular Aβ42 amyloid peptide by mutation of presenilins PS1 and PS2
Authors: Takeda Kazuya , Araki Wataru , Tabira Takeshi
Published: January 2004

The accumulation of amyloid β‐peptide (Aβ) in the brain is a critical pathological process in Alzheimer's disease (AD). Recent studies have implicated intracellular Aβ in neurodegeneration in AD. To investigate the generation of intracellular Aβ, we established human neuroblastoma SH‐SY5Y cells stably expressing wild‐type amyloid precursor protein (APP), Swedish mutant APP, APP plus presenilin 1 (PS1) and presenilin 2 (PS2; wild‐type or familial AD‐associated mutant), and quantified intracellular Aβ40 and Aβ42 in formic acid extracts by sensitive Western blotting. Levels of both intracellular Aβ40 and Aβ42 were 2–3‐fold higher in cells expressing Swedish APP, compared with those expressing wild‐type APP. Intracellular Aβ42/Aβ40 ratios were approximately 0.5 in these cells. These ratios were increased markedly in cells expressing mutant PS1 or PS2 compared with those expressing their wild‐type counterparts, consistent with the observed changes in secreted Aβ42/Aβ40 ratios. High total levels of intracellular Aβ were observed in cells expressing mutant PS2 because of a marked elevation of Aβ42. Immunofluorescence staining additionally revealed more intense Aβ42 immunoreactivity in mutant PS2‐expressing cells than in wild‐type cells, which was partially colocalized with immunoreactivity for the trans‐Golgi network and endosomes. The data collectively indicate that PS mutations promote the accumulation of intracellular Aβ42, which appears to be localized in multiple subcellular compartments.
Superior tactile performance and learning in professional pianists: evidence for meta‐plasticity in musicians
Authors: Ragert Patrick , Schmidt Alexander , Altenmüller Eckart , Dinse Hubert R.
Published: January 2004

Musician's brains constitute an interesting model for neuroplasticity. Imaging studies demonstrated that sensorimotor cortical representations are altered in musicians, which was assumed to arise from the development of skilled performance. However, the perceptual consequences of the cortical changes remain elusive. Here we ask whether cortical reorganization induced by professional musical skill training is paralleled by the evolution of other, unrelated perceptual abilities. We therefore studied psychophysically tactile spatial acuity as an indirect marker of cortical changes in professional pianists and non‐musician control subjects using a simultaneous two‐point discrimination paradigm. We show that long‐lasting piano practising resulted in lower spatial discrimination thresholds in comparison to non‐musicians. In musicians, individual discrimination thresholds were linearly correlated with the daily training duration, indicating a direct link between tactile acuity and the degree of piano practising. To investigate whether the superior acuity in pianists is subject to further improvement, we used a Hebbian stimulation protocol of tactile coactivation known to improve spatial tactile acuity. Three hours of coactivation further reduced their discrimination thresholds. The coactivation‐induced gain in pianists was significantly larger in comparison to control subjects and correlated with the years of heavy daily practising (>3 h/day), but not with the total years including casual playing. Our results suggest that despite already high‐level performance in pianists, Hebbian learning was more effective in musicians than in controls. This implies stronger capacities for plastic reorganization and points to enhanced learning abilities implicating a form of meta‐plasticity in professional pianists.