bluuebunny/crossref_metadata_2025 huggingface dataset:
Asymptomatic Intracranial Hypertension in Disorders of CSF Circulation in Childhood – Treated and Untreated
Authors: Johnston Ian H. , Duff John , Jacobson Erica E. , Fagan Elizabeth
Published: April 2003

Twelve patients are described who were found to have asymptomatic intracranial hypertension monitored over an extended (6 months to 6 years) period. There were three groups: 5 patients with treated hydrocephalus with an apparently functioning shunt, 4 patients with untreated hydrocephalus, clinically and radiologically nonprogressive, and 3 patients with pseudotumor cerebri, 2 treated and 1 untreated. Although the magnitude of the intracranial pressure changes varied, all patients had abnormal baseline pressures together with repeated A and B waves. In no case was there any clinical manifestation of raised intracranial pressure and in all cases ventricular size remained constant over the period of evaluation. The clinical and pathophysiological implications of these findings are discussed.
Intraventricular Pressure Dynamics in Ventriculocholecystic Shunting: A Telemetric Study
Authors: Frim David M. , Lathrop Dawn , Chwals Walter J.
Published: April 2003

Extracranial cerebrospinal fluid shunting is the current mainstay of therapy for hydrocephalus. The generally preferred extracranial site for cerebrospinal fluid absorption is the peritoneal space; however, the cardiac atrium and the pleura are also commonly used. On occasion other CSF recipient sites, such as the gallbladder, are used secondarily when the more common absorptive spaces are unavailable or unsuitable. The gallbladder, though, exhibits its own pressure dynamics in response to physiological stimuli. The effects of gallbladder contraction on intraventricular pressure (IVP) in the presence of a ventriculocholecystic (VGB) shunt are unknown. We had the opportunity to place a VGB shunt in a 4-year-old child who was coupled to a noninvasive telemonitor. After a period of acclimation, we examined the IVP dynamics of that shunting system both pre- and postprandially. We found that before ingestion of food, the gallbladder provides a CSF recipient site similar to that of the peritoneal space. However, after ingestion of a meal containing fat, we found that IVP rose more than 10 cm water in a stereotypic fashion consistent with postprandial gallbladder contraction. The increase in IVP lasted for several hours reaching a peak at approximately 75 min postprandially. We conclude that the VGB shunt is a viable alternative for extracranial cerebrospinal fluid shunting; however, one must be aware of the peculiar dynamics of this shunt in relation to food ingestion and the potential for unusually high IVPs.
Supratentorial Ependymoma in Children
Authors: Vinchon Matthieu , Soto-Ares Gustavo , Riffaud Laurent , Ruchoux Marie-Magdeleine , Dhellemmes Patrick
Published: April 2003

The clinical and pathological characteristics of supratentorial ependymomas (STE) in children are not well identified in the literature, because most series deal with ependymomas regardless of their location or the age of the patient. As a result, the pathological description of the disorder is still debated. We therefore reviewed our cases of children operated for STE and compared them with cases of infratentorial ependymomas (ITE) to provide a better characterization of STE and suggest guidelines for treatment. From 1985 to 1999, we operated 18 children for STE, almost half of which developed with no connection to the ventricular system. Intraoperative bleeding and infiltration of the basal ganglia prevented total removal in 4 cases and were the main causes of operative mortality and morbidity. The 5-year overall survival and recurrence-free survival rates were 54 and 37%, respectively, and were highly affected by the extent of resection, but not by histological grade. Because of the high recurrence rate, we recommend systematic postoperative irradiation limited to the tumor site for all high-grade tumors in older children, and reoperation after subtotal removal and for recurrences.
Predictors of Acute Child and Family Outcome following Traumatic Brain Injury in Children
Authors: Anderson Vicki A. , Catroppa Cathy , Haritou Flora , Morse Sue , Pentland Linda , Rosenfeld Jeffrey , Stargatt Robyn
Published: April 2003

Objective: To examine the relative contributions of injury severity, level of physical and cognitive disability, child behavior and family function to short-term outcome 6 months following traumatic brain injury (TBI) in children. Design: Prospective, longitudinal, between-group design, comparing preinjury and postinjury measures of functional outcome across three levels of injury severity. Subjects: One hundred and twelve children, aged 2–12 years admitted to the Royal Children’s Hospital, Melbourne, with a diagnosis of TBI. The sample was divided into three groups, according to injury severity: mild TBI (n = 31), moderate TBI (n = 52) and severe TBI (n = 29). Children with a history of neurologic, developmental and psychiatric disorder were excluded from participation. Main Outcome Measures: Levels of postinjury functioning in the following domains: physical function, cognitive ability (incorporating intellect, memory and attention), behavioral and family functioning, and level of family burden. Results: A clear dose-response relationship for physical and cognitive outcomes was found, with severe TBI associated with greater impairment of physical, intellectual, memory and attentional function. For psychosocial outcome, results were less clearly linked to injury severity. Preinjury behavioral and family functioning were closely related to postinjury function in these domains, with an interaction identified between family function and child behavior at 6 months postinjury. Family functioning remained unchanged postinjury, although level of burden was high, and predicted by injury severity, functional impairment and postinjury behavioral disturbance. Conclusions: These results suggest ongoing functional problems for the child and significant family burden 6 months following TBI. The nature and severity of physical and cognitive problems are most closely related to injury severity, with family functioning and child behavior better predicted by psychosocial and premorbid factors.
Future Directions for Therapy of Childhood Hydrocephalus: A View from the Laboratory
Authors: Del Bigio Marc R.
Published: April 2003

A personal perspective on the study of experimental models of hydrocephalus is offered. Many animal models are available; each has its own advantages and disadvantages. Detailed study of more than one model is needed to clarify the pathogenesis of hydrocephalus-induced brain damage in the immature nervous system. Further information is needed about the mechanism of axonal injury in periventricular tissue, changes in the extracellular compartment, water dynamics within brain tissue, the role of neurotrophic factors in hydrocephalus, and the sites of injury in chronic ‘arrested’ hydrocephalus. Insight into the multifactorial nature of the brain damage may allow us to develop supplemental pharmacologic therapies, which could protect the brain and promote recovery in the pre- and postshunt period.
Vagal Nerve Stimulation for Status epilepticus
Authors: Winston Ken R. , Levisohn Paul , Miller Bradford R. , Freeman Jane
Published: April 2003

Refractory generalized convulsive status epilepticus in a 13-year-old boy was halted by left vagal nerve stimulation. Over the next 1.5 years, seizures have continued at a rate and severity which is significantly better than it had been in the year before insertion of the stimulator.
Traumatic Atlanto-Occipital Dislocation in Children
Authors: Houle Paul , McDonnell Dennis E. , Vender John
Published: April 2003

Traumatic atlanto-occipital dislocation is seen in approximately 25% of fatal pediatric trauma. This was previously considered to be a rare and fatal entity, however with improvements in resuscitation in the field, many patients who previously might have died are now evaluated in the hospital. Treatment of atlanto-occipital instability is internal fixation. Many authors have advocated supplemental external immobilization with a halo vest. However, there are several circumstances where the application of a halo vest is undesirable. Thus a method of internal fixation and fusion that is rigid enough not to require supplemental external orthosis is necessary. We present 2 cases of atlanto-occipital dislocation which were treated with Locksley intersegmental tie bar occipital cervical fusion. Both patients achieved solid fusion without supplemental halo bracing, and made complete neurologic recoveries. Traumatic atlanto-occipital dislocation is a potentially survivable injury that requires aggressive resuscitation in the field, a high index of suspicion and early definitive surgical stabilization.
Vagus Nerve Stimulation for Control of Intractable Seizures in Childhood
Authors: Amar Arun Paul , Levy Michael L. , McComb J. Gordon , Apuzzo Michael L.J.
Published: April 2003

Vagus nerve stimulation (VNS) is gaining increasing popularity and credibility as a treatment option for children with intractable epilepsy. VNS offers several advantages over extant treatments. Its efficacy is maintained during prolonged stimulation, and seizure control actually improves with time. There is no associated cognitive impairment and no adverse drug interactions. Unlike cerebral surgery, VNS is a potentially reversible form of therapy. The computer-controlled characteristic of the device permits complete and involuntary treatment compliance. VNS is safe and well-tolerated. Its side effects are generally transient and mild, and no physiologic perturbations have been reported despite extensive monitoring. Serious adverse events are rare, and no deaths have been attributed to VNS therapy itself or to the technique of surgical insertion. In this article, we discuss the theoretical background behind VNS and review the clinical studies that substantiate its long-term safety, feasibility, tolerability and potential efficacy in children with refractory epilepsy.
Open Thoracic Meningocele Associated with Amniotic Band Syndrome
Authors: Jackson Thad
Published: April 2003

We present a case of an infant born with an open thoracic meningocele secondary to an amniotic band. Although there have been several case reports of encephalocele, anencephaly, closed meningocele and a case of tethered cord associated with amniotic band syndrome (ABS), there has yet to be a report of an open meningocele associated with ABS. The patient remained neurologically intact after the repair of his meningocele. His postoperative course was complicated by meningitis with subsequent hydrocephalus necessitating ventriculoperitoneal shunt placement.
Horizontal Sacrum as an Indicator of a Tethered Spinal Cord
Authors: Tubbs R. Shane , Wellons III John C. , Bartolucci Alfred A. , Blount Jeffrey P. , Oakes W. Jerry
Published: April 2003

The horizontal sacrum has never been described as an indicator of a tethered spinal cord following myelomeningocele closure. We retrospectively analyzed 30 children with a myelomeningocele for this progressive change and its correlation with symptoms. At least two lateral radiographs over time were examined and the lumbosacral angle (LSA) was measured. We found that the majority of these children had an LSA that was greater than would be expected in patients with late and decreased ambulatory abilities. Also, we observed that the LSA was often inappropriately increased at the time many of these patients presented with symptoms indicative of a tethered spinal cord. We hypothesize that the LSA in this group of children is altered by a tethered spinal cord and that the horizontal nature of the sacrum may predate the clinically appreciable symptoms of a tethered spinal cord.
Effect of Isosorbide Dinitrate on Nitric Oxide Synthase under Hypoxia
Authors: Jiang Hou-Bo , Yoneyama Hirohito , Furukawa Aizo , Hamamoto Tatsuhichiro , Takahara Jirou , Ichikawa Yoshiyuki
Published: April 2003

Nitric oxide synthase (NOS) catalyzes nitric oxide (NO) formation from L-arginine in the presence of molecular oxygen and NADPH. NO is involved in the regulation of microvasculature. Isosorbide dinitrate (ISDN) and glyceryl trinitrate (GTN) have been widely used as vasodilators to treat acute myocardial ischemia, their biological effects being due to the release of NO. In this investigation, the effects of ISDN and GTN on NOS activity in the presence or absence of oxyhemoglobin under hypoxia and normoxia were studied. The apparent Km values for molecular oxygen were 21.6 ± 1.5 and 9.4 ± 1.3 µmol/l for nNOS and eNOS, respectively. ISDN liberated NO in a concentration- and pH-dependent manner, but no differences between hypoxia and normoxia were observed. The NO release from ISDN was also measured directly by an electron spin resonance spectral method with N-(dithiocarboxy)sarcosine-Fe complex as a NO-trapping agent. ISDN increased nNOS and eNOS activities in the presence of 30 µmol/l oxyhemoglobin under hypoxia, while it did not affect nNOS and eNOS activities under normoxia. In the absence of oxyhemoglobin, ISDN inhibited nNOS and eNOS activities under both hypoxic and normoxic experimental conditions. The rate of oxygen release from oxyhemoglobin under hypoxia was increased 3 times in the presence of 1 mmol/l ISDN. In contrast to ISDN, GTN could not release NO spontaneously, and it also did not affect nNOS and eNOS activities in the absence or presence of 30 µmol/l oxyhemoglobin under both hypoxic and normoxic conditions. These results indicated that the NO release from ISDN is different from that of GTN, and the increase of NOS activity by ISDN in the presence of oxyhemoglobin under hypoxia is ascribed to the increase in molecular oxygen concentration.
Reinforcing Effects of MDMA (‘Ecstasy’) in Drug-Naive and Cocaine-Trained Rats
Authors: Ratzenboeck Elisabeth , Saria Alois , Kriechbaum Norbert , Zernig Gerald
Published: April 2003

3,4-Methylenedioxymethamphetamine (MDMA; ‘ecstasy’) is one of the most prevalent illegal drugs of abuse among European adolescents, a population not generally experienced with respect to ‘hard’ drugs such as cocaine. We, therefore, determined the reinforcing effect of intravenously self-administered MDMA in a fixed ratio 1 time-out 150 s schedule of reinforcement in rats that were truly drug naive and compared it to cocaine-trained rats. The reinforcing effect of MDMA [0.032–10 mg/(kg·injection)] did not differ between drug-naive rats and cocaine-trained ones. MDMA sensitized the animals to its own rate-increasing effect but not to that of cocaine. When MDMA was tested after cocaine, there was no carryover of cocaine’s reinforcing effect to that of MDMA, suggesting that MDMA and cocaine produce distinct interoceptive stimuli in rats.
Acute Antidepressant-Like and Antianxiety-Like Effects of Tryptophan in Mice
Authors: Wong P.T.-H. , Ong Y.P.
Published: April 2003

The antidepressant-like, antianxiety-like and sedative effects of tryptophan (TRP), in the absence and presence of p-chlorophenylalanine (p-CPA), and melatonin were studied in mice using the forced-swimming test, open-field test and activity cage, respectively. Single-dose TRP caused an antidepressant-like effect dose dependently up to 125 mg/kg. No significant effect was observed, however, when the TRP dose was increased to 250 mg/kg, i.e. a reversal of effect occurred at high dose. With p-CPA pretreatment, the effects observed at 125 and 250 mg/kg TRP were similar to those obtained at 50 and 125 mg/kg without p-CPA pretreatment, respectively. Melatonin also caused an antidepressant-like effect in a similar manner, but appeared to be less potent than TRP. These results strongly indicate that the antidepressant-like effect of TRP was due to its conversion to 5-hydroxytryptamine (5-HT). An antianxiety-like effect was observed for TRP only at 250 mg/kg dose together with p-CPA pretreatment, while no sedative effect was observed at all. In contrast, melatonin did not produce any antianxiety-like effect, but produced sedation at 200 mg/kg dose. It may be concluded that the antianxiety-like effect of TRP is unrelated to 5-HT and melatonin formation, but associated with TRP itself or, perhaps, with other anxiolytic metabolites.
Role of Nitric Oxide and Mucus in Ischemia/Reperfusion-Induced Gastric Mucosal Injury in Rats
Authors: Kim Hyeyoung , Hwan Kim Kyung
Published: April 2003

The present study aims at investigating the role of nitric oxide (NO) on the oxidative damage in gastric mucosa of rats which received ischemia/reperfusion (I/R) and its relation to mucus. NO synthesis modulators such as L-arginine and NG-nitro-L-arginine methyl ester (L-NAME) were injected intraperitoneally to the rats 30 min prior to I/R which was induced by clamping the celiac artery and the superior mesenteric artery for 30 min and reperfusion for 1 h. As a result, I/R increased lipid peroxide production and decreased the contents of glutathione (GSH), cGMP and mucus as well as GSH peroxidase activities of gastric mucosa. I/R decreased the activity and protein of NO synthase (NOS) in gastric mucosa. Pretreatment of L-arginine, a substrate for NOS, prevented I/R-induced alterations of gastric mucosa. However, L-NAME, an NOS inhibitor, deteriorated oxidative damage induced by I/R. In conclusion, NO has an antioxidant defensive role on gastric mucosa by maintaining mucus, GSH and GSH peroxidase, which were related to preservation of cGMP and NOS in gastric mucosa.
Dual Effect of the Antianginal Drug Fendiline on Bladder Female Transitional Carcinoma Cells: Mobilization of Intracellular Ca2+ and Induction of Cell Death
Authors: Jan Chung-Ren , Yu Chia-Cheng , Huang Jong-Khing
Published: April 2003

The effect of fendiline, an antianginal drug, on cytosolic free Ca2+ levels ([Ca2+]i) in populations of bladder female transitional carcinoma (BFTC) cells was explored using fura-2 as a Ca2+ indicator. Fendiline at concentrations between 3 and 200 µmol/l increased [Ca2+]i in a concentration-dependent manner and the signal saturated at 100 µmol/l. The [Ca2+]i signal was biphasic, with an initial rise and a slow decay. Ca2+ removal inhibited the Ca2+ signal by about half in peak amplitude. Adding 3 mmol/l Ca2+ increased [Ca2+]i in cells pretreated with 100 µmol/l fendiline in Ca2+-free medium, suggesting that fendiline induced Ca2+ influx via capacitative Ca2+ entry. In Ca2+-free medium, pretreatment with 1 µmol/l thapsigargin (an endoplasmic reticulum Ca2+ pump inhibitor) to deplete the endoplasmic reticulum Ca2+ store inhibited most of the 100 µmol/l fendiline-induced internal Ca2+ release; and conversely, pretreatment with 100 µmol/l fendiline partly inhibited 1 µmol/l thapsigargin-induced Ca2+ release. This indicates that the major internal Ca2+ store of fendiline-induced [Ca2+]i increases is located in the endoplasmic reticulum. The Ca2+ release induced by 100 µmol/l fendiline may be partly mediated by inositol 1,4,5-trisphosphate, because the [Ca2+]i increase was inhibited by 50% by inhibiting phospholipase C with 2 µmol/l U73122. Fendiline (100 µmol/l) decreased cell viability by 12–44% after being added to cells for 2– 30 min. Together, the findings indicate that in BFTC cells, fendiline exerts a dual effect: mobilization of intracellular Ca2+ and induction of cell death.
Biochemical, Electrophysiological and Neurohormonal Studies with B-20991, a Selective 5-HT1A Receptor Agonist
Authors: Caicoya Anne G. , Beneytez María E. , Delgado Mercedes , Manzanares Jorge , López-Rodríguez María L. , Benhamu Belinda , Morcillo María J. , Pozo Miguel A. , Rubia Francisco J. , Fuentes José A.
Published: April 2003

Different receptor subtypes mediate the effects produced by serotonin (5-HT) in mammals. Besides their proved anxiolytic action, agonists of the 5-HT1A receptor subtype show prospects as antidepressants or neuroprotective agents in case of ischemia. In order to better define the pharmacological profile and determine the selectivity for the 5-HT receptor type, the properties of the new 5-HT1A receptor agonist 2[[4-(o-methoxyphenyl)piperazin-1-yl]-methyl]-1.3-dioxoperhydroimidazo[1.5-a]pyridine (B-20991), an arylpiperazine derivative, have now been further studied. B-20991 was found to antagonize the forskolin-induced increase of cAMP synthesis in a HeLa cell line transfected with the human 5-HT1A in a process sensitive to the selective blocker N-[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]-N-2-pyridinyl-cyclohexanecarboxamide maleate (WAY 100635). Additionally, B-20991 showed a dose-dependent inhibition of the spontaneous on-going activity of serotonin (5-HT) neurons in the dorsal raphe nucleus in rats, an effect that was reversed by treatment with WAY 100635. This, together with the fact that the hypothermia induced by B-20991 in mice was also antagonized by WAY 100635, suggests that the new compound acts upon somatodendritic 5-HT1A receptors. Additional activation of 5-HT1A postsynaptic receptors was indicated by the increase of corticosterone plasma levels induced by B-20991 in the rat. These results demonstrate that B-20991 is a selective 5-HT1A receptor agonist acting both pre- and postsynaptically, which represents an useful pharmacological tool to study 5-HT1A-receptor-mediated effects.
Pharmacological Characterization of a Novel 5-HT4 Receptor Agonist, TS-951, in vitro
Authors: Kajita Sumiyo , Ito Chika , Kawamura Reiko , Yasuda Shoji , Isobe Yoshihiko , Fukushima Kiyomi
Published: April 2003

The pharmacological effect of a novel selective 5-HT4 receptor agonist, TS-951 (N-[endo-8-(3-hydroxypropyl)-8-azabicyclo[3.2.1]oct-3-yl]-1-isopropyl-2-oxo-1,2-dihydro-3-quinolinecarboxamide) was investigated in vitro. TS-951 potently inhibited specific [3H]GR113808 binding both in guinea-pig striatum and in mouse brain. The affinity of TS-951 for the 5-HT4 receptor was higher than those of other agonists, 5-HT, cisapride, mosapride and renzapride. On the longitudinal muscle of the guinea-pig ileum, TS-951 caused a concentration-dependent increase in the amplitude of electrically induced submaximal twitch contractions. On the longitudinal muscle of the guinea-pig distal colon, TS-951 also caused concentration-dependent contractions. TS-951 is a high-affinity, selective and potent 5-HT4 receptor agonist. This compound therefore can be considered as a useful pharmacological tool for investigating 5-HT4 receptor-mediated events.
Diazepam Stimulates Migration and Phagocytosis of Human Neutrophils: Possible Contribution of Peripheral-Type Benzodiazepine Receptors and Intracellular Calcium
Authors: Marino Franca , Cattaneo Simona , Cosentino Marco , Rasini Emanuela , Di Grazia Laura , Fietta Anna Maria , Lecchini Sergio , Frigo Gianmario
Published: April 2003

In isolated human neutrophils, diazepam (10 nmol/l to 10 µmol/l) concentration-dependently increased migration and phagocytosis. Diazepam-induced migration and phagocytosis were inhibited by the peripheral benzodiazepine receptor (PBR) antagonist PK11195 (10 µmol/l). The PBR agonist Ro5-4864 (10 nmol/l to 10 µmol/l) did not affect migration but slightly enhanced phagocytosis, while clonazepam, which binds to the central-type benzodiazepine receptors but has no affinity for PBRs, was ineffective on both parameters up to 10 µmol/l. Phagocytosis induced by diazepam or Ro5-4864 was inhibited by the Ca2+ channel blocker L-verapamil (10 µmol/l), which however did not affect the action of diazepam on migration. Competition binding experiments performed by fluorescent staining of PBRs showed that diazepam directly interacts with PBRs on human neutrophils. Both diazepam and Ro5-4864 (10 nmol/l to 10 µmol/l) induced a rise of intracellular free Ca2+ concentrations ([Ca2+]i), which was inhibited by PK11195 (10 µmol/l) and L-verapamil (10 µmol/l) and prevented by extracellular Ca2+ chelation with EGTA (5 mmol/l). In conclusion, experimental evidence indicates that in human neutrophils diazepam stimulates both migration and phagocytosis through activation of PBRs. Diazepam-induced [Ca2+]i changes depend on a PBR-operated, L-verapamil-sensitive increase in the plasma membrane permeability and subsequent extracellular Ca2+ entry, and contribute to diazepam-induced phagocytosis. On the contrary, the effect of diazepam on migration seems to occur through Ca2+-independent mechanisms.
Gastroprokinetic Effect and Mechanism of SK-896, a New Motilin Analogue, during the Interdigestive Period in Conscious Dogs
Authors: Tsukamoto Katsura , Tagi Yoshihiko , Nakazawa Toru , Takeda Motohiro
Published: April 2003

SK-896 [(Leu13)motilin-Hse] is a new human motilin analogue synthesized from Escherichia coli using a biotechnological method. We investigated the gastrointestinal motor-stimulating effect of SK-896 and the mechanism of this effect using implanted force transducers in conscious dogs. Infusion of SK-896 during phase I in the interdigestive state induced interdigestive migrating contractions like motility in the gastroduodenum. The motility index (MI0–20) of gastric antrum motor activity induced by SK-896 was increased dose dependently (r = 0.830, p < 0.001), and the MI0–20 induced by SK-896 at a dose of 0.25 µg/kg/h for 20 min was the same as that for spontaneous phase III contractions. The SK-896-induced MI0–20 was significantly decreased by atropine, hexamethonium, dopamine, granisetron, and yohimbine. Conversely, ketanserin, phentolamine, timolol, and naloxone did not have significant effects on SK-896-induced MI0–20. The effects of these drugs on human motilin (0.25 µg/ kg/h for 20 min) induced MI0–20 were the same as those of SK-896. These results indicate that SK-896 induces gastrointestinal motility during the interdigestive period in dogs with regulation of acetylcholine release from the cholinergic nerve terminal via the parasympathetic nervous system in the same fashion as human motilin.
Availability of Learned Helplessness Test as a Model of Depression Compared to a Forced Swimming Test in Rats
Authors: Takamori Kazuaki , Yoshida Shigeru , Okuyama Shigeru
Published: April 2003

This study was designed to evaluate the antidepressant activity of various antidepressants using the learned helplessness test (LH) or the forced swimming test (FS) in rats. Repeated treatment of the tricyclic antidepressants imipramine (10 mg/kg, p.o.), clomipramine (0.625 mg/kg, p.o.), amitriptyline (10 mg/kg, p.o.) and amoxapine (20 mg/kg, p.o.) reduced the number of escape failures in the LH group, respectively. Repeated treatment of an atypical antidepressant, mianserin (2.5 and 5 mg/kg, p.o.), and one of the selective serotonin reuptake inhibitors (SSRI), fluvoxamine (1.25 mg/kg, p.o.), also reduced the number of escape failures in the LH group. In the FS, repeated treatment of imipramine (5, 10 mg/kg, p.o.), amitriptyline (5, 10 mg/kg, p.o.) and mianserin (10 mg/kg) significantly decreased the duration of immobility time. On the other hand, repeated treatment of amoxapine (5–20 mg/kg), clomipramine (0.1325–1.25 mg/kg, p.o.) and fluvoxamine (0.3125–1.25 mg/kg, p.o.) failed to decrease the duration of immobility time in the FS group. In conclusion, these results suggest that the LH group is sensitive to agents with a variety of antidepressant properties compared to the FS group in rats.
Oral Self-Administration of Ethanol and Cocaine in Rats
Authors: Grathwohl C. , Dadmarz M. , Vogel W.H.
Published: April 2003

Most laboratory animal studies on self-administration of drugs of abuse use only one drug, whereas humans frequently engage in polydrug use. For this reason, we studied oral self-administration of ethanol (E) and cocaine (C) with the free choice bottle method using a single drug alone, a combination (E and C in separate bottles) or a mixture of both drugs in a single bottle. Young female rats (45 days) consumed similar amounts of C if offered alone (12.4 ± 7.5 mg/kg/day), in the presence of ethanol (10.6 ± 3.5) or as E/C mixture (8.0 ± 4.0). They also consumed similar amounts of E if offered alone (3.8 ± 1.6 ml/kg/day), in the presence of C (2.3 ± 0.8) or E/C mixture (2.4 ± 1.1). Voluntary consumption of both drugs varied markedly among animals but was consistent in a given rat. No correlation occurred between consumption of E and C. Young male rats behaved similarly and consumed similar amounts of E and C alone, in combination and as mixture. While E consumption was similar, C consumption was higher in female rats. Old male rats (180 days) were similar to young male rats. The presence of a saccharin solution as a distracter had no effect on intake of E or C in young females but reduced E intake only in young male rats. In young animals, prior voluntary consumption of either E or C had no effect on subsequent voluntary consumption of the same or other drug offered in combination. These results indicate that this model may be useful to study polydrug use in humans, that consumption of both E and C is strongly controlled by an individual animal, that prior exposure to one drug had no or little effect on a subsequent consumption of the same or other drug in combination and that intake of E or C seems to be independent of each other suggesting two independent reward centers.
Partial Agonistic Properties of (±)-Pindolol at Atypical β-Adrenoceptors in the Guinea Pig Gastric Fundus
Authors: Horinouchi Takahiro , Koike Katsuo
Published: April 2003

(±)-Pindolol ([1-(1H-indol-4-yloxy)-3-[(1-methylethyl)- amino]-2-propanol)]) is a partial agonist at atypical β-adrenoceptors in the guinea pig gastric fundus. (±)-Pindolol induced concentration-dependent relaxation in this tissue. However, the relaxant responses of (±)-pindolol were not antagonized by a combination of the selective β1-adrenoceptor antagonist atenolol (10–4 mol/l) and the selective β2-adrenoceptor antagonist butoxamine (10–4 mol/l). In the presence of both atenolol and butoxamine, the nonselective β1-, β2- and β3-adrenoceptor antagonist (±)-bupranolol (10–5–10–4 mol/l) caused a concentration-dependent rightward shift of the concentration-response curves for (±)-pindolol. Schild plot analyses of (±)-bupranolol against (±)-pindolol gave the pA2 value of 5.46 ± 0.03 and Schild slope was not significantly different from unity. Furthermore, (±)-pindolol (10–5 mol/l) weakly but significantly antagonized the relaxant responses to catecholamines ((–)-isoprenaline, (–)-noradrenaline and (–)-adrenaline), a selective β3-adrenoceptor agonist BRL37344 ((R*,R*)-(±)-4-[2-[(2-(3-chlorophenyl)-2-hydroxyethyl)amino]propyl]phenoxyacetic acid sodium salt) and a nonconventional partial β3-adrenoceptor agonist (±)-CGP12177A ([4-[3-[(1,1-dimethylethyl)amino]-2-hydroxypropoxy]-1,3-dihydro-2H-benzimidazol-2-one] hydrochloride). These results suggest that (±)-pindolol acts as a partial agonist at atypical β-adrenoceptors in the guinea pig gastric fundus.
Inhibitory Effect of Egualen Sodium: A New Stable Derivative of Azulene on Histamine Release from Mast Cell-Like Cells in the Stomach
Authors: Akagi Masaaki , Matsui Nobuaki , Mochizuki Seiichiro , Tasaka Kenji
Published: April 2003

We studied the inhibitory effect of egualen sodium (ES) (sodium 3-ethyl-7-isopropyl-1-azulenesulfonate 1/3 hydrate, KT1–32), a new derivative and more stable compound than azulene, on histamine release from the mucosal histaminocytes and elucidated the mechanism for this action. ES prevented the histamine release from isolated mast cell-like cells of the guinea pig stomach induced by A23187 in a dose-dependent fashion. ES dose-dependently inhibited the histamine release from lung pieces of sensitized guinea pigs induced by an antigen-antibody reaction. ES also inhibited histamine release from rat peritoneal mast cells induced by compound 48/80 or antigen-antibody reaction. ES exhibited the membrane stabilizing activity on DPPC liposomes. These findings suggest that ES may prevent histamine release from histaminocytes induced by various stimuli and the stabilizing action of the cell membrane may be responsible for the inhibition of histamine release.
Molecular and Pharmacokinetic Evaluation of Rat Hepatic and Gastrointestinal Cytochrome P450 Induction by Tamoxifen
Authors: Cotreau Monette M. , von Moltke Lisa L. , Harmatz Jerold S. , Greenblatt David J.
Published: April 2003

Tamoxifen (TAM) is a first-line endocrine treatment for all stages of postmenopausal breast cancer. The cytochrome P450 (CYP) enzymes catalyze the majority of TAM’s primary metabolism, producing N-desmethyltamoxifen (DMT) and 4-hydroxytamoxifen (4-OH-TAM) in both humans and rats. CYP 3A isoforms are the predominant subfamily involved in the formation of DMT and recent studies have shown that TAM induces hepatic forms of these enzymes. TAM’s inductive effect on gastrointestinal CYP 3A has not been previously reported. The current studies investigated TAM’s induction of CYP isoforms (3A and 2B) in female rat gastrointestinal and hepatic tissue at the mRNA, protein, and catalytic level. Since previous studies have not addressed whether TAM induction causes changes to the overall pharmacokinetics (PKs), a rat PK model was used to determine if TAM induced its own metabolism, and/or the metabolism of a CYP 3A substrate, midazolam (MDZ). Phenobarbital (PB) and/or dexamethasone (DEX) were used as positive controls for all studies. TAM significantly induced, or caused a trend towards induction of all studied parameters for hepatic CYP 3A and 2B, whereas intestinal CYP 3A and 2B analysis did not show significant induction by TAM at any level. A study evaluating time-dependent alterations in the PK profile of TAM showed no change in apparent oral clearance (Clapp) during two weeks of chronic dosing with TAM. However, the Clapp for MDZ was shown to trend towards an increase after two weeks of dosing with TAM, in a second PK study. These combined investigations suggest that TAM is an inducer of rat hepatic CYP 3A and 2B isoforms, and this agent has the potential of influencing the PK of coadministered 3A substrates.
Calcium-Antagonistic Activity of Sumatriptan in the Rat Anococcygeus Muscle
Authors: Emre-Aydıngöz Selda , Kocaefe Çetin , Tuncer Meral
Published: April 2003

The relaxant effect of sumatriptan, a 5-HT1B/1D receptor agonist, on the rat anococcygeus muscle was investigated. Sumatriptan induced concentration-dependent relaxations of the phenylephrine-precontracted rat anococcygeus muscle. NG-nitro-L-arginine, methylene blue, glibenclamide, tetrodotoxin, indomethacin, GR 113808, GR 55562, methysergide, ketanserin, ICS 205930, clozapine, methiothepin, metergoline, mesulergine, and ritanserin did not inhibit the relaxations induced by sumatriptan. Sumatriptan converted calcium-induced contractions into relaxations in the preparations depolarized by a calcium-free, high-potassium solution. In membrane preparations obtained from the rat anococcygeus muscle, the basal rate of cAMP production by adenylate cyclase was 4.77 ± 0.02 pmol/mg protein/min (n = 15). The enzyme activity was increased to 104 ± 51.7 pmol/mg protein/min by forskolin (10–4 mol/l), but did not change in the presence of sumatriptan. The mRNA expression of 5-HT1B, 5-HT1D, and 5-HT7 receptors was not observed in the rat anococcygeus muscle. The results indicate that sumatriptan causes relaxation of the precontracted rat anococcygeus muscle by a calcium-antagonistic activity.
Oxidative Stress Induced Cytokine Production in Isolated Rat Pancreatic Acinar Cells: Effects of Small-Molecule Antioxidants
Authors: Seo Jeong Yeon , Kim Hyeyoung , Seo Jeong Taeg , Kim Kyung Hwan
Published: April 2003

Reactive oxygen species are considered important regulators in the pathogenesis and in the development of pancreatitis. The transcription factor nuclear factor ĸB (NF-ĸB) is activated by reactive oxygen species and regulates the gene expressions of inflammatory cytokines. The present study investigates (1) the susceptibility of isolated rat pancreatic acinar cells to oxidant attacks produced by adenosine diphosphate/ferrous iron, hypoxanthine/xanthine oxidase, and neutrophils primed with 4β-phorbol 12β-myristate 13α-acetate (PMA) and (2) the potential of small-molecule antioxidants (N-acetylcysteine, β-carotene, rebamipide, allopurinol) and superoxide dismutase (SOD) to prevent such injury and oxidant-mediated NF-ĸB activation and inflammatory cytokine production in the cells. As a result, oxidative stress resulted in a time-dependent increase in lipid peroxide production in pancreatic acinar cells which was inhibited by small-molecule antioxidants and SOD. PMA-primed neutrophils induced NF-ĸB activation and increased the production of cytokines (IL-6, TNF-α) in the cells. This was in parallel with lipid peroxide production. Small-molecule antioxidants and SOD inhibited NF-ĸB activation and cytokine production in acinar cells caused by PMA-primed neutrophils. In conclusion, oxidative stress activates NF-ĸB, resulting in upregulation of inflammatory cytokines in pancreatic acinar cells. Small-molecule antioxidants might be clinically useful anti-inflammatory agents by inhibiting oxidant-induced cytokine production.
Alteration of M3 Subtype Muscarinic Receptors in the Diabetic Rat Urinary Bladder
Authors: Tong Yat-Ching , Cheng Juei-Tang
Published: April 2003

The M3 receptor (M3-mAChR) is the major muscarinic subtype in the animal bladder responsible for detrusor contraction. The alterations in its protein quantity and biosynthesis during diabetic cystopathy were investigated. 3-month-old male Wistar rats were divided into two groups: (1) 2-week diabetic rats and (2) normoglycemic control rats. Diabetes was induced by a single intravenous injection of 60 mg/kg streptozotocin. The amount of M3 receptor protein in the rat bladder body tissue was measured by Western immunoblotting using monoclonal antibodies. For determination of M3 muscarinic receptor mRNA in the bladder tissue, the method of Northern blotting was employed. The results of the Western immunoblotting showed that the amount of M3-mAChR protein in the diabetic bladder was significantly increased by about 70.2 ± 8.5% when compared to the control bladder (p < 0.05, n = 8). Northern blotting demonstrated a 54.7 ± 6.0% increase of M3-mAChR mRNA in the diabetic bladder (p < 0.05, n = 8). The findings of the present study demonstrated an upregulation of M3-mAChR biosynthesis in the diabetic urinary bladder. This phenomenon offers an explanation of the increased contractility after muscarinic stimulation of the detrusor muscle of diabetic animals.
Binding of the Active Metabolite of Chloral Hydrate, 2,2,2-Trichloroethanol, to Serum Albumin Demonstrated Using Tryptophan Fluorescence Quenching
Authors: Solt Ken , Johansson Jonas S.
Published: April 2003

Chloral hydrate, a sedative/hypnotic agent widely used in the pediatric population, is converted to the active metabolite 2,2,2-trichloroethanol (TCE) in the liver. Tryptophan fluorescence quenching has been used previously to show that halothane and chloroform bind saturably to serum albumin, and a similar approach is used here to demonstrate that TCE also binds to albumin. TCE quenches the steady-state tryptophan fluorescence of bovine serum albumin (BSA) in a concentration-dependent, saturable manner with a KD = 3.3 ± 0.3 mmol/l. Unlike halothane and chloroform, however, TCE also elicits a concentration-dependent blue-shift in the fluorescence emission spectrum of BSA and human serum albumin. This indicates that TCE induces a conformational change in the protein, causing the tryptophan to experience a change in its chemical environment, thus shifting the peak of the emission spectrum. Circular dichroism spectroscopy revealed a decrease in the α-helical content of BSA from 65.8 ± 0.4 to 62.9 ± 0.6% when TCE was present at a concentration of 30 mmol/l, providing further evidence for a conformational change. There is evidence that TCE potentiates the action of ligand-gated ion channels such as the GABAA and 5-HT3 receptors, and the present results suggest that anesthetic alcohols may act by binding to these proteins and inducing structural changes that may in turn alter protein function.
A Novel Attribute of Enoxaparin: Inhibition of Monocyte Adhesion to Endothelial Cells by a Mechanism Involving Cell Adhesion Molecules
Authors: Manduteanu Ileana , Voinea Manuela , Capraru Monica , Dragomir Elena , Simionescu Maya
Published: April 2003

Enoxaparin is a low molecular weight heparin, widely accepted as anticoagulant or antithrombotic drug, and is likely to have a role in acute inflammation. To evaluate the anti-inflammatory potential of enoxaparin, we investigated the direct effect of the drug on the activation of endothelial cells. For this purpose we set up an in vitro system in which cultured valvular endothelial cells (VEC) activated by tumor necrosis factor alpha or lipopolysaccharide were exposed to a monocytic cell line; these conditions induced a significant adhesion of monocytes to VEC. Adhesion assays, ELISA, and flow cytometric analysis revealed that pretreatment with enoxaparin, at a relevant plasma concentration (16 µg/ml), acts upon activation of VEC by inhibition of lipopolysaccharide-induced E-selectin expression and tumor necrosis factor stimulated ICAM-1 expression, thus reducing monocyte adhesion to VEC. These results suggest a novel function of enoxaparin, namely to protect VEC from activation and inhibiting the expression of cell adhesion molecules.
Diltiazem Reduces Apoptosis in Rat Hepatocytes Subjected to Warm Hypoxia-Reoxygenation
Authors: Crenesse Dominique , Tornieri Karine , Laurens Marina , Heurteaux Catherine , Cursio Raffaele , Gugenheim Jean , Schmid-Alliana Annie
Published: April 2003

Interruption of hepatic blood flow is necessary in surgery, but the liver is sensitive to ischemia and reperfusion. Hypoxia induces an increase in intracellular calcium concentration. In previous studies, we have shown that hypoxia-reoxygenation (H/R) increased calcium influx and induced JNK1/SAPK1 activation which was involved in the triggering of apoptosis. The aim of this study was to demonstrate that diltiazem, a calcium inhibitor, reduced JNK1/SAPK1 activation and consequently could decrease H/R-induced apoptosis. Experiments were performed, in the presence of diltiazem, on primary cultured rat hepatocytes, subjected to warm H/R phases and in a liver ischemia-reperfusion model. The activation status of JNK1/SAPK1 was evaluated by immunoprecipitation and immunohistolocalisation experiments, while apoptosis was assessed by measuring caspase activity and by TUNEL labeling. Diltiazem inhibited H/R-induced JNK1/SAPK1 activation and decreased apoptosis. It could be used to improve postoperative liver function.
The Production of English Vowels by Fluent Early and Late Italian-English Bilinguals
Authors: Piske Thorsten , Flege James Emil , MacKay Ian R.A. , Meador Diane
Published: April 2003

The primary aim of this study was to determine if fluent early bilinguals who are highly experienced in their second language (L2) can produce L2 vowels in a way that is indistinguishable from native speakers’ vowels. The subjects were native speakers of Italian who began learning English when they immigrated to Canada as children or adults (‘early’ vs. ‘late’ bilinguals). The early bilinguals were subdivided into groups differing in amount of continued L1 use (early-low vs. early-high). In experiment 1, native English-speaking listeners rated 11 English vowels for goodness. As expected, the late bilinguals’ vowels received significantly lower ratings than the early bilinguals’ vowels did. Some of the early-high subjects’ vowels received lower ratings than vowels spoken by a group of native English (NE) speakers, whereas none of the early-low subjects’ vowels differed from the NE subjects’ vowels. Most of the observed differences between the NE and early-high groups were for vowels spoken in a nonword condition. The results of experiment 2 suggested that some of these errors were due to the influence of orthography.
Is There a Gender Difference in a Factorial Structure of the Positive and Negative Syndrome Scale?
Authors: Hayashi Naoki , Igarashi Yoshito , Yamashina Mitsuru , Suda Kiyoko
Published: April 2003

By means of the multisample structured means strategy, we examined gender differences in a five-factorial structure model of Positive and Negative Syndrome Scale (PANSS) ratings of 308 patients of both sexes with DSM-IV schizophrenia with comparable age at investigation and overall symptomatic severity across sex. The test indicated that the factors and component symptoms were common across sex, whereas the factor loadings might be different. However, the model that incorporated the difference in the factor loadings did not improve model fit indices. Therefore, it is concluded that this investigation elicited only minimal gender differences, and on the whole confirmed the PANSS five-factor structure for both sexes.
Coping Measurement and the State Effect of Depression and Anxiety in Psychiatric Outpatients
Authors: Uehara Toru , Sakado Kaoru , Sato Tetsuya , Takizawa Ryu
Published: April 2003

The relationship between coping styles and mental health has received considerable attention, but the state effects on coping measures in a clinical sample are not well known. This study investigated changes in scores on the Coping Inventory for Stressful Situations between two treatment phases (acute and remitted phase) in 49 outpatients with major depression or anxiety disorders. Task-oriented coping changed significantly between the treatment phases in both depressive and anxious patients, as analyzed by two-way multivariate analysis of variance. Results from repeated measures of multivariate analysis of covariance indicated that task-oriented coping was influenced by depression and emotion-oriented coping was influenced by anxiety. Avoidance-oriented coping did not change significantly over time in either depressive or anxiety disorders controlled for depressive and anxiety symptoms. The results of this study suggest that depressive or anxiety symptoms and treatment phase affect coping measurement.
Detecting Alcohol-Related Problems among General Hospital Patients with Heart Disease
Authors: Lykouras Lefteris , Rontos Ioannis , Rontos Kostas , Katsaras Aris , Markoulis Theodore , Papasteriades Evangelos , Christodoulou George N.
Published: April 2003

Background: Certain epidemiologic studies suggest that moderate alcohol consumption decreases the risk of coronary heart disease. However, long-term excessive alcohol drinking is considered a major cause for a significant incidence of heart disease. Identifying alcohol-related problems among inpatients with cardiac disease is important. Methods: In this study, 209 male and 137 female inpatients with cardiac disease were screened for alcohol-related problems using the CAGE questionnaire. Associations of alcohol-related problems with sociodemographic and clinical variables were also investigated. Results: Fifty-seven patients (16.5%) scoring positively on the CAGE questionnaire were considered as having alcohol-related problems. Logistic regression analysis revealed that alcohol-related problems were associated with sex (p = 0.00), age (p = 0.0497), and educational level (p = 0.0524). Men less than age 50, with cardiac disease and of lower education level should be considered at high risk for abnormal drinking. The probability increases from 5.2% for the whole sample to 41.9% for the group with these specific characteristics. Conclusions: The characteristics are useful for constructing a profile of the cardiology patient who is more likely to have alcohol-related problems. Early identification and vigorous and holistic treatment of these patients is important for secondary prevention of alcohol-related problems.