bluuebunny/crossref_metadata_2025_split huggingface dataset:
Susceptibility to kainate‐induced seizures under dietary zinc deficiency
Authors: Takeda Atsushi , Hirate Maki , Tamano Haruna , Nisibaba Daisuke , Oku Naoto 
Published: June 2003

AbstractZinc homeostasis in the brain is altered by dietary zinc deficiency, and its alteration may be associated with the etiology and manifestation of epileptic seizures. In the present study, susceptibility to kainate‐induced seizures was enhanced in mice fed a zinc‐deficient diet for 4 weeks. When Timm's stain was performed to estimate zinc concentrations in synaptic vesicles, Timm's stain in the brain was attenuated in the zinc‐deficient mice. In rats fed the zinc‐deficient diet for 4 weeks, susceptibility to kainate‐induced seizures was also enhanced. When the release of zinc and neurotransmitters in the hippocampal extracellular fluid of the zinc‐deficient rats was studied using in vivo microdialysis, the zinc concentration in the perfusate was less than 50% of that of the control rats and the increased levels of zinc by treatment with kainate were lower than the basal level in control rats, suggesting that vesicular zinc is responsive to dietary zinc deficiency. The levels of glutamate in the perfusate of the zinc‐deficient rats were more increased than in the control rats, whereas the levels of GABA in the perfusate were not at all increased in the zinc‐deficient rats, unlike in the control rats. The present results demonstrate an enhanced release of glutamate associated with a decrease in GABA concentrations as a possible mechanism for the increased seizure susceptibility under zinc deficiency.
Ether‐linked analogue of 2‐arachidonoylglycerol (noladin ether) was not detected in the brains of various mammalian species
Authors: Oka Saori , Tsuchie Akiko , Tokumura Akira , Muramatsu Mayumi , Suhara Yoshitomo , Takayama Hiroaki , Waku Keizo , Sugiura Takayuki 
Published: June 2003

Abstract2‐Eicosa‐5′,8′,11′,14′‐tetraenylglycerol (2‐AG ether, HU310, noladin ether) is a metabolically stable ether‐linked analogue of 2‐arachidonoylglycerol (2‐AG), an endogenous cannabinoid receptor ligand. 2‐AG ether has been used as a valuable experimental tool by a number of investigators. Recently, several groups reported that 2‐AG ether is present in mammalian brains. We examined in detail whether 2‐AG ether actually exists in the brains of various mammalian species. We found that 2‐AG ether is not present, at least in an appreciable amount, in the rat brain by gas chromatography‐mass spectrometry analysis and fluorometric high performance liquid chromatography analysis. The level of 2‐AG ether in the rat brain was below 0.2 pmol/g brain, if at all present. Similar results were obtained for the mouse brain, hamster brain, guinea‐pig brain and pig brain. The fact that 2‐AG ether was not detected in the brains of various mammalian species is consistent with the fact that an ether bond is formed through enzymatic replacement of the fatty acyl moiety of 1‐acyl dihydroxyacetone phosphate by a fatty alcohol, the resultant 1‐O‐alkyl dihydroxyacetone phosphate being a common intermediate of the biosynthesis of ether‐linked lipids in mammalian tissues. It is rather questionable whether 2‐AG ether is present in appreciable amounts in the brain and acts as an ‘endogenous’ cannabinoid receptor ligand.
Post‐transcriptional suppression of pathogenic prion protein expression in Drosophila neurons
Authors: Deleault Nathan R. , Dolph Patrick J. , Feany Mel B. , Cook Meghan E. , Nishina Koren , Harris David A. , Supattapone Surachai 
Published: June 2003

AbstractA wealth of evidence supports the view that conformational change of the prion protein, PrPC, into a pathogenic isoform, PrPSc, is the hallmark of sporadic, infectious, and inherited forms of prion disease. Although the central role played by PrPSc in the pathogenesis of prion disease is appreciated, the cellular mechanisms that recognize PrPSc and modulate its production, clearance, and neural toxicity have not been elucidated. To address these questions, we used a tissue‐specific expression system to express wild‐type and disease‐associated PrP molecules heterologously in Drosophila melanogaster. Our results indicate that Drosophila brain possesses a specific and saturable mechanism that suppresses the accumulation of PG14, a disease‐associated insertional PrP mutant. We also found that wild‐type PrP molecules are maintained in a detergent‐soluble conformation throughout life in Drosophila brain neurons, whereas they become detergent‐insoluble in retinal cells as flies age. PG14 protein expression in Drosophila eye did not cause retinal pathology. Our work reveals the presence of mechanisms in neurons that specifically counterbalance the production of misfolded PrP conformations, and provides an opportunity to study these processes in a model organism amenable to genetic analysis.
The Arg617–Arg618 cleavage site in the C‐terminal domain of PC1 plays a major role in the processing and targeting of the enzyme within the regulated secretory pathway
Authors: Bernard Natacha , Kitabgi Patrick , Rovere‐Jovene Carole 
Published: June 2003

AbstractThe C‐terminal domain of the prohormone convertase PC1 is involved in targeting of the enzyme to secretory granules in neuroendocrine cells and is subsequently processed in this compartment at an Arg617‐Arg618 site. Three other dibasics are found in the C‐terminal domain of mouse PC1. Here, we examined the role of the four dibasics in targeting PC1 to secretory granules. All 15 possible combinations of dibasic mutations were performed. Wild‐type (WT) and mutant PC1 were stably expressed in neuroendocrine PC12 cells that lacked endogenous PC1. Processing, secretion and intracellular localization of PC1 and its mutants were analyzed. Leaving intact Arg617‐Arg618 and mutating any combination of the three other dibasics yielded proteins that were stored and processed in secretory granules, similarly to WT PC1. Mutating Arg617‐Arg618 alone or with any one of the three remaining dibasics generated proteins that were efficiently stored in secretory granules but were not processed further. Mutating Arg617‐Arg618 with more than one of the remaining dibasics produced proteins that reached the TGN but were not stored in secretory granules and exited the cells through the constitutive secretory pathway. These data demonstrate that the Arg617‐Arg618 plays a prominent role in targeting PC1 to secretory granules.
Molecular neuroadaptations in the accumbens and ventral tegmental area during the first 90 days of forced abstinence from cocaine self‐administration in rats
Authors: Lu Lin , Grimm Jeff W. , Shaham Yavin , Hope Bruce T. 
Published: June 2003

AbstractCocaine self‐administration is associated with a propensity to relapse in humans and reinstatement of drug seeking in rats after prolonged withdrawal periods. These behaviors are hypothesized to be mediated by molecular neuroadaptations within the mesolimbic dopamine system. However, in most studies of drug‐induced neuroadaptations, cocaine was experimenter‐delivered and molecular measurements were performed after short withdrawal periods. In the present study, rats were trained to self‐administer intravenous cocaine or oral sucrose (a control non‐drug reward) for 10 days (6‐h/day) and were killed following 1, 30, or 90 days of reward withdrawal. Tissues from the accumbens and ventral tegmental area (VTA) were assayed for candidate molecular neuroadaptations, including enzyme activities of cAMP‐dependent protein kinase (PKA) and adenylate cyclase (AC), and protein expression of cyclin‐dependent kinase 5 (cdk5), tyrosine hydroxylase (TH) and glutamate receptor subunits (GluR1, GluR2 and NMDAR1). In the accumbens of cocaine‐trained rats, GluR1 and NMDAR1 levels were increased on days 1 and 90, while GluR2 levels were increased on days 1 and 30, but not day 90; PKA activity levels were increased on days 1 and 30, but not day 90, while AC activity, TH and cdk5 levels were unaltered. In the VTA of cocaine‐trained rats, NMDAR1 levels were increased for up to 90 days, while GluR2 levels were increased only on day 1; TH and Cdk5 levels were increased only on day 1, while PKA and AC activity levels were unaltered. Cocaine self‐administration produces long‐lasting molecular neuroadaptations in the VTA and accumbens that may underlie cocaine relapse during periods of abstinence.
Two novel methods for the determination of CYP1A2 activity using the paraxanthine/caffeine ratio
Authors: Doude van Troostwijk Lous J. A. E. , Koopmans Richard P. , Guchelaar Henk‐Jan 
Published: June 2003

AbstractCytochrome P450 1A2 (CYP1A2) plays an important role in drug metabolism. Provocation with caffeine is used to estimate CYP1A2 activity, but in most tests a long period of caffeine abstinence has to be taken into account. We compared two novel methods with the currently applied test.The pharmacokinetic (PK) parameters of caffeine and paraxanthine were estimated in eight caffeine‐taking healthy volunteers by fitting serum concentration–time data to a two‐compartment PK model. Then a three‐step approach was followed. Step 1: The caffeine administration regimens of three provocation methods, which differ by their periods of abstinence, together with the PK parameters of each volunteer, were entered in a PK simulation program and the molecular ratio of the paraxanthine/caffeine concentration (P/C molratio) of each method was estimated for the individual volunteers. Step 2: For each method a relationship for the population between the caffeine clearance (Clc) and the corresponding P/C molratio was empirically established. Step 3: The true caffeine clearance (Clc tr) of each volunteer, as found by fitting the individual PK curve, was compared for all three methods with the clearance estimated from the individual P/C molratio using the relationship of step 2. The predictive values for Clc of the three methods did not differ significantly from Clc tr. For the three methods the values for bias were 6.7, 4.3 and 3.1%, respectively and for precision they were 12.3, 20.6 and 17.8%.We conclude that the two novel methods of caffeine provocation show good predictive performance for Clc when compared with the conventional method. Abstaining from caffeine for a long period is not necessary to estimate CYP1A2 activity (using the P/C molratio) accurately.
Differences in the effects of extended‐release aspirin and plain‐formulated aspirin on prostanoids and nitric oxide in healthy volunteers
Authors: De La Cruz J. P. , González‐Correa J. A. , Guerrero A. , Márquez E. , Martos F. , Sánchez de la Cuesta F. 
Published: June 2003

SummaryThis study was designed to evaluate the effects of extended‐release aspirin on platelet aggregation and the production of prostanoids and nitric oxide. The participants in this double blind, randomized and crossover study were 20 healthy volunteers. Interventions were 150 mg of plain‐formulated aspirin (PFASA) and 150 mg of extended‐release aspirin (ERASA). Blood samples were collected before and 10, 20, 60, 120, 240, 480 and 1440 min after the first dose; 3, 7 and 14 days after daily administration and 24 h after the last dose. The main measures were platelet aggregometry, thromboxane B2, 6‐keto‐prostaglandin (PG) F1α and nitric oxide in each control. Platelet aggregation was inhibited by 50% with ERASA, and by 77% with PFASA. No differences were found in chronic treatment. Thromboxane B2 was inhibited more by the latter (51–67%), but 90% inhibition was observed in both groups after 3 days. The levels of 6‐keto‐PGF1α was reduced by 20% with ERASA and by 58% with PFASA. Nitric oxide production increased in both groups, but after 24 h, and 7–14 days, elevated concentrations of nitric oxide were found only in the ERASA. The antiplatelet effects of ERASA provide pharmacological advantages (greater prostacyclin synthesis and prolonged increase in nitric oxide production) over those provided by the plain formulation.
The [14C‐N‐methyl]‐erythromycin breath test dosimetry complies with the French regulations for radiation safety
Authors: Salvat Cécile , Mouly Stéphane , Rizzo‐Padoin Nathalie , Knellwolf Anne‐Laure , Simoneau Guy , Duet Michèle , Nataf Valérie , Bailliart Olivier , Bergmann Jean‐François 
Published: June 2003

AbstractThe [14C‐N‐methyl]‐erythromycin breath test (14C‐ERMBT) is one of the most valuable probes for liver cytochrome P450‐3A4 activity in humans. In order to extend the use of this test in France, we herein provide safety data regarding either patient dosimetry or worker exposure to [14C‐N‐methyl]‐erythromycin. In order to determine the maximum radiation exposure for patient and nuclear medicine technician following one intravenous 14C‐ERMBT [111 kiloBequerel (kBq)], we have used the dosimetric data gathered in animal studies and extrapolated to humans using a weight‐based method, approximate data provided by the French Society of Radioprotection and erythromycin pharmacokinetics in humans, considering always the worst conditions for the patient and worker exposure determination. The radioactivity administered to a patient after one 14C‐ERMBT was equal to 108.8 kBq (i.e. 98% of the total radioactivity in the 14C‐erythromycin vial) leading to a patient effective dose of 20 microsievert (μSv) and a maximum effective dose after 14CO2 inhalation by the exposed worker of 16 μSv compared with a mean individual annual effective dose from natural and artificial radioactivity exposure of 3500 μSv in France. The 14C‐ERMBT is safe and complies with the European regulations regarding the administration of 14C‐labelled compounds in humans. It can therefore be used in clinical research in France without any particular safety requirement.
Drug metabolism and disposition in children
Authors: Strolin Benedetti M. , Baltes E.L. 
Published: June 2003

AbstractKey factors undergoing maturational changes accounting for differences in drug metabolism and disposition in the pediatric population compared with adults are reviewed. Gastric and duodenal pH, gastric emptying time, intestinal transit time, bacterial colonization and probably P‐glycoprotein are important factors for drug absorption, whereas key factors explaining differences in drug distribution between the pediatric population and adults are membrane permeability, plasma protein concentration and plasma protein characteristics, endogenous substances in plasma, total body and extracellular water, fat content, regional blood flow and probably P‐glycoprotein, mainly that present in the gut, liver and brain. As far as drug metabolism is concerned, important differences have been found in the pediatric population compared with adults both for phase I enzymes [oxidative (e.g. cytochrome CYP3A7 vs. CYP3A4 and CYP1A2), reductive and hydrolytic enzymes] and phase II enzymes (e.g. N‐methyltransferases and glucuronosyltransferases). Finally, key factors undergoing maturational changes accounting for differences in renal excretion in the pediatric population compared with adults are glomerular filtration and tubular secretion. It would be important to generate information on the developmental aspects of renal P‐glycoprotein and of other renal transporters as done and still being done with the different isozymes involved in drug metabolism.
Self‐medication: from European regulatory directives to therapeutic strategy
Authors: Bergmann Jean‐François 
Published: June 2003

AbstractSelf medications are drugs which can be used without a physician's advice or supervision. There is a clear emerging patient demand for efficient drugs available without prescription. This review summarizes the regulatory rules regarding the status of self‐medication drugs in Europe and describes some situations where specific clinical trials are needed for a new drug to be registered as a self medication. These drugs not only have to offer a very positive safety profile but also a well‐established level of efficacy. A nonprescription drug can only be proposed in situations where the patient himself can make a self‐assessment of the medical condition and its follow‐up. These products must be safe even in the event of incorrect use and must offer clear and complete information contributing to a proper use, i.e. a definition of situations where a physician's advice is necessary. For registration as an ‘over‐the‐counter’ drug, specific efficacy trials may be conducted in real self‐medication situation especially when the target populations, the dosage or the indications in self medication are not the same as those evaluated previously when the drug in question had prescription status. Specific pharmacovigilance is needed and the patient, pharmacist and physician encouraged to report any adverse events. A safety survey may be necessary in some situations such as insomnia or emergency contraception. It is important for the patient, pharmacist and public health in general to distinguish the efficient and safe self medications from the nonvalidated, nonevaluated alternative medicines.
Ultrastructural clues for glutamate‐induced necrosis in parietal and cerebellar neurons
Authors: Eşrefoğlu Mukaddes , Gepdiremen Akçahan , Kuruş Meltem 
Published: June 2003

AbstractGlutamate excitotoxicity has been postulated to underlie the neuronal death that occurs after ischemia. The most sensitive tissues to ischemic injury are hippocampus and cerebellum, whereas cerebrum is more resistant. We studied the glutamate‐induced ultrastructural alterations in rat parietal and cerebellar neurons comparatively. We observed that glutamate (45 min, 10−7 m) causes considerable nuclear, mitochondrial and cytoplasmic changes in both the neuron types. Mitochondrial and nuclear changes were particularly more severe in cerebellar granular, than the ones in parietal neurons. It has been concluded that glutamate induces necrotic changes in both parietal and cerebellar neurons. But cerebellar cortex was found to be more sensitive to glutamate excitotoxicity than cerebral cortex. We suggest that mitochondrial damage is, probably, an important factor in neuron necrosis, which is mediated by glutamate excitotoxicity.
Antihypertensive effects of the essential oil of Alpinia zerumbet and its main constituent, terpinen‐4‐ol, in DOCA‐salt hypertensive conscious rats
Authors: Lahlou Saad , Interaminense Leylliane Fátima Leal , Leal‐Cardoso José Henrique , Duarte Gloria Pinto 
Published: June 2003

AbstractThe present study investigated the hypotensive responses to intravenous (i.v.) treatment with the essential oil of Alpinia zerumbet (EOAZ) and its main constituent, terpinen‐4‐ol (Trp‐4‐ol), in the experimental model of deoxycorticosterone‐acetate (DOCA)‐salt hypertensive rat.In both DOCA‐salt hypertensive and uninephrectomized, normotensive rats, i.v. bolus injections of EOAZ (1–20 mg/kg) or Trp‐4‐ol (1–10 mg/kg) decreased mean aortic pressure (MAP) in a dose‐related manner. However, hypotensive responses to Trp‐4‐ol were significantly greater than those evoked by the same doses of EOAZ (1–10 mg/kg). Treatment with DOCA‐salt significantly enhanced the maximal percentage decreases in MAP evoked by EOAZ or Trp‐4‐ol. Likewise, both maximal percentage and absolute decreases in MAP elicited by i.v. injection of the ganglion blocker, hexamethonium (30 mg/kg), were significantly greater in DOCA‐salt hypertensive than in control rats. In DOCA‐salt hypertensive rats, neither hexamethonium (30 mg/kg, i.v.) nor methylatropine (1 mg/kg, i.v.) pretreatment affected the enhancement of EOAZ‐induced hypotension.These results show that i.v. treatment with either EOAZ or Trp‐4‐ol dose‐dependently decreases blood pressure in conscious DOCA‐salt hypertensive rats, and this action is enhanced when compared with uninephrectomized controls. This enhancement could be related mainly to an increase in EOAZ‐induced vascular smooth muscle relaxation rather than to enhanced sympathetic nervous system activity in this hypertensive model. The data further support our previous hypothesis that hypotensive effects of EOAZ are partially attributed to the actions of Trp‐4‐ol.
Caffeine as a promoter of analgesic‐associated nephropathy – where is the evidence?
Authors: Fox Johannes M. , Siebers Ute 
Published: June 2003

AbstractIndividual groups of nephrologists – in their responsibility for their patients – initiated a most controversial discussion whether or not caffeine – coformulated to analgesics – might initiate or sustain analgesic overdosing. The original sources (data) of such suspicion have got lost during the debate of the last two decades. Therefore, it seemed to be appropriate to investigate the original data background and the reasons why nephrologists started to suspect caffeine as a stimulant of analgesic overdosing by employing a systematic and exhaustive review of primary nephrological publications. Their selection followed a precise selection plan, including all epidemiological studies on analgesic‐associated nephropathy, the original papers of all groups having been involved in those studies, further originals from the mainly involved countries (academically, politically), and any literature thereof cited as a proof. The following results emerged from the investigation:The epidemiological studies warranted no conclusion about a role of caffeine in prompting excessive analgesic use.The identified groups of nephrologists provided not substantial data to advocate the said suspicion, except for the observation of a preferential choice of phenacetin‐containing combinations, especially powder preparations.Only two cited original data sources revealed drug‐seeking behaviour with phenacetin‐containing preparations which subsided, after phenacetin was banned from the respective markets.Conclusively, it appears that there is no substantial data to support a pivotal role of caffeine in initiating or sustaining analgesic overdosing. However, there is strong data that phenacetin, by its psychotropic properties, may have caused drug‐seeking behaviour and thus led to analgesic overdosing. This conclusion is convincingly supported by thorough pharmacokinetic investigations.Note: All caffeine‐related statements within the reviewed literature have been collected in tables (referred to asTable SX) which are provided in full text for check on the following website:http://www.blackwellpublishing.com/products/journals/suppmat/FCP/FCP174/FCP174sm.htm
Evaluation of the Harmonic Scalpel for Laparoscopic Bilateral Ovariectomy in Standing Horses
Authors: Düsterdieck Katja F. , Pleasant R. Scott , Lanz Otto I. , Saunders Geoffrey , Howard Rick D. 
Published: June 2003

Objective—To evaluate use of the Harmonic Scalpel (Ethicon Endo‐Surgery Inc., Cincinnati, OH) for performing laparoscopic bilateral ovariectomy in standing horses.Study Design—Experimental study.Animals—Eight mares aged 2–20 years and weighing 410–540 kg.Methods—Standing laparoscopic bilateral ovariectomy was performed in 8 mares with normal reproductive tract anatomy. The Harmonic Scalpel (an ultrasonically activated instrument) was used to simultaneously transect and obtain hemostasis of the ovarian pedicle. Necropsy was performed on 4 mares 3 days after surgery and 4 mares 30 days after surgery. Gross and histopathologic evaluation of the ovarian pedicles was performed to characterize tissue reaction.Results—Complete hemostasis of the ovarian pedicles was obtained in all mares. Median transection time for the ovarian pedicle was 28 minutes. Postoperative complications included transient fever, moderate subcutaneous emphysema, and incisional seroma formation. On necropsy examination, there were no signs of generalized peritonitis, postoperative hemorrhage, or adhesion formation. Mild to moderate acute inflammation and scar formation with moderate chronic inflammation at the ovarian pedicle was found at 3 and 30 days. Median depth of coagulation necrosis at 3 days was 2.87 mm.Conclusions—The Harmonic Scalpel appears to provide reliable hemostasis of the ovarian pedicle during elective laparoscopic ovariectomy in horses.Clinical Relevance—The Harmonic Scalpel represents a safe alternative to other methods of hemostasis during elective laparoscopic ovariectomy in horses.