Ion involvement in memory formation: the potential role of astrocytes.
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Animals↗
Biomedical subjects
K T Ng
Publications and source records attributed to K T Ng.
Disposition of bepridil in laboratory animals and man.
1. The disposition and pharmacokinetics of bepridil (Bp) were studied in mouse, rat, rabbit, rhesus monkey, and man. Bp was essentially completely absorbed by all species. 2. Maximum plasma Bp concentrations were achieved within 2 h of drug administration. Linear but non-proportional, dose-related increases in the area under the curve (AUC) for plasma Bp vs. time were noted after increasing oral doses of Bp.HCl to rats (30-300 mg/kg) and monkeys (25-200 mg/kg). 3. Daily administration of Bp.HCl to rats (100 mg/kg per day for 15 days) and monkeys (200 mg/kg per day for 13 days) produced no statistically significant changes in Bp pharmacokinetic parameters. 4. Oral plasma clearance (CLp) of Bp was very low in man (ca. 0.93 l/h per kg) compared to experimental animals (14.8-63.8 l/h per kg). Terminal elimination half-lives were 1.5-2.0 h for mouse and rat, ca. 4.4 h for monkey and ca. 48 h for man. 5. Bp and a total of 12 metabolites were identified and quantified. Metabolite formation in the five species was adequately described by four interrelated pathways, namely, aromatic hydroxylation, followed by N-dealkylation, N-debenzylation, and N-acetylation. Metabolites produced by this pathway included 4-hydroxy-Bp, N-benzyl-4-aminophenol, 4-aminophenol, and N-acetyl-4-aminophenol. Comparison of the proposed pathways revealed qualitative similarity among species.
Administration, Oral↗
Meningeal carcinomatosis from solid tumors: clinical analysis of 42 cases.
From January 1984 to June 1990, we observed 42 patients with meningeal carcinomatosis, 20 men and 22 women, aged 21 to 80 years (median age, 53 years). The two most common primary malignancies were lung cancer (50%) and breast cancer (31%). Sixty-four per cent was adenocarcinoma. On the first lumbar puncture, 86% had malignant cells in the cerebrospinal fluid. The findings of brain computed tomography were hydrocephalus (62%), contrast enhancement in the cerebral sulci or basal cisterns (31%), concomitant parenchymal metastases (15%) and normal scan (18%). In five out of seven cases, myelography showed irregular filling defects over the spinal cord or cauda equina. Treatment results were evaluated in 24 patients. Eight received radiation therapy (RT) alone, and 16 had combined therapy with RT plus intrathecal methotrexate (IT MTX). Of the patients who received RT alone, only one patient with lung carcinoma was stabilized clinically. Of the cases receiving combined therapy, seven improved clinically. Six of these were patients with breast carcinoma who received IT MTX via Ommaya reservoir. The latter had a median survival of 23 weeks. The follow-up period of the entire group of patients ranged from one day to 50 weeks. The median survival was four weeks. Based on this study, combined therapy with RT and IT MTX is indicated for breast carcinoma with meningeal carcinomatosis, but the therapeutic effects are uncertain for lung carcinoma and other malignancies.
Adult↗
Prognosis of thymic carcinoma: analysis of 16 cases.
Primary thymic carcinoma is a rare malignant neoplasm which arises from the thymic epithelium. Between May 1982 and September 1990, 16 patients with thymic carcinomas, diagnosed at Chang Gung Memorial Hospital, were reviewed. Their ages ranged from 19 to 75 years, with a median of 40 years. Males predominated (male to female ratio was 11:5). The most common presenting symptoms were chest pain, cough, body weight loss and dyspnea. No paraneoplastic syndromes were seen. Chest roentgenograms of 15 patients revealed a mediastinal mass, but a definitive diagnosis could not be made until surgery. Adjacent mediastinal tissues were invaded, or adhered to, by all the tumors. Six distinct histologic types were found, squamous cell carcinoma being the most common (seven cases). The primary treatment of surgical resection was attempted in 14 patients, but only in five cases could the tumors be completely resected; two had a biopsy only. Radiotherapy, with or without chemotherapy, given postoperatively, achieved additional local control in seven of the nine partially resected patients (77%). Distant metastasis occurred in nine of 16 patients (56%). Lymph nodes, bone and lung were the most common metastatic sites. Chemotherapy with cisplatin and/or adriamycin-based regimens was given to patients who had distant metastasis, but the responses were unsatisfactory. The overall survival at one, three and five years was 88%, 51% and 31%, respectively. The median survival was 30 months. The median survival of patients with pure squamous cell carcinoma (> 49 months) was superior to that of patients with other histologic types (18 months; p < 0.01).
Adult↗
Molecular mechanisms of memory formation.
Studies with neonate chicks, trained on a passive avoidance task, suggest that at least two shorter-term memory stages precede long-term, protein synthesis-dependent memory consolidation. Posttetanic neuronal hyperpolarization arising from two distinct mechanisms is postulated to underlie formation of these two early memory stages. Maintenance of the second of these stages may involve a prolonged period of hyperpolarization brought about by phosphorylation of particular proteins. A triggering mechanism for long-term consolidation is postulated to occur at a specific time during the second stage, and may involve reinforcement-contingent release of neuronal noradrenaline stimulating cAMP-dependent intracellular processes. The possibility that astroglia may have a critical role to play in these early stages of memory processing is raised.
Animals↗
Brain metabolic activity associated with long-term memory consolidation.
The use of day-old chickens trained on a single-trial passive avoidance task provides a useful paradigm for investigations into cellular mechanisms underlying memory formation. Pharmacological intervention studies indicate that there are three temporally identifiable stages of memory processing leading to the consolidation of information for this task. These stages, designated as short-term (STM; up to 15 min), intermediate-term (ITM; 15-55 min), and long-term (LTM; more than 55 min) memory, have been found to be sequentially dependent (Ng and Gibbs, 1989). In addition, ITM appears to consist of two physiologically distinguishable phases, A and B. Evidence in this laboratory suggests that the crossover between these ITM phases (at 30 min after training) represents a critical time-point for the triggering of LTM.
Animals↗
Possible noradrenergic involvement in training stimulus intensity.
Day-old chicks trained on a single trial passive discrimination avoidance task using a concentrated chemical aversant, methyl anthranilate (MeA), have been shown to exhibit three stages of memory processing: short, intermediate and long term. A similar learning task with the aversant diluted to 20% in ethanol leads to short- and intermediate-term memory only, but not to long-term memory. The emergence of long-term memory has been shown to be associated with the production of a nonenergy-dependent phase of the intermediate memory stage. Subcutaneous administration of propranolol proved capable of inhibiting this nonenergy-dependent phase of memory under a number of training regimes: strongly reinforced training, and with weakly reinforced training presented twice or coupled with a selected dose of the stress-related hormone ACTH. This study supports the notion that there is a phase of memory that occurs prior to the protein synthesis-dependent phase of memory which is susceptible to interference by drugs affecting noradrenergic processes and which may be associated with the intensity of the training stimulus.
Animals↗
Forebrain noradrenaline concentration following weakly reinforced training.
Day-old chicks trained on a single-trial discriminated passive avoidance task using a concentrated taste aversant, methyl anthranilate, have been shown to exhibit three stages of memory processing; short-, intermediate-, and long-term memory. If the aversant is diluted to 20% v/v methyl anthranilate in absolute ethanol, only the short-term and some of the intermediate stage are observed. In this study we investigated the whole forebrain levels of noradrenaline in response to differing intensities of the training experience. The results show a profound difference in the level of whole forebrain NA at all training-sacrifice intervals for the trained as compared to the untrained controls, except at 15- and 20-minute posttraining, when a substantial reduction in the level of NA was achieved under all training conditions. Furthermore, subjects which received treatments which resulted in the emergence of behavioural evidence of long-term memory tended to have higher levels of whole-forebrain NA at 30 minutes after initial training. This is the time when we have postulated that triggering of protein synthesis associated with long-term memory formation takes place.
Animals↗
Memory consolidation of weak training experiences by hormonal treatments.
Day-old chicks trained on a single-trial passive discrimination avoidance task using a concentrated chemical aversant, methyl anthranilate (MeA), have been shown to exhibit three stages of memory processing; short-, intermediate- and long-term. A similar learning task with the aversant diluted to 20% in ethanol leads to short-and intermediate-term memory, but no long-term memory. Subcutaneous administration of selected doses of the stress-related hormones, noradrenaline, ACTH and vasopressin in close temporal proximity to the training trial, produced long-term memory in chicks trained on the weakly reinforced task, mimicking the outcome of strongly reinforced learning and of retraining with the weakly reinforced task reported previously. These effects are shown to be associated with the production of a nonenergy-dependent phase of the intermediate memory stage, postulated to be necessary for long-term memory consolidation.
2,4-Dinitrophenol↗
Activity-related rise in extracellular potassium concentration in the brain of 1-3-day-old chicks.
The concentration of K+ [( K+]) was measured in the cerebrospinal fluid (CSF) and in the extracellular fluid [( K+]e) in the medial forebrain of two-day-old chicks by means of K(+)-sensitive microelectrodes (K-ISM). The K-ISM potential in the CSF was compared with that in artificial CSF with 3, 4 or 6 mmol/l of [K+]. The [K+] found in CSF was 3.79 +/- 0.57 (n = 8), in the hyperstriatum accessorium (HA) 3.70 +/- 0.32 (n = 13) and in the neostriatum (N) 3.51 +/- 0.32 (n = 13; mmol/l; mean +/- SEM). Trains of local electrical stimuli (10-100 Hz, 30 sec) applied to the surface of the forebrain increased [K+]e in both HA and N by 11-13 mmol/l. Increases in [K+]e in the ectostriatum (E) of 5-6 mmol/l was found in response to electrical stimulation (30-100 Hz, 5-10 sec) of the contralateral optic nerve, and of about 2 mmol/l by applying pressure to the bulb. In chicks adapted to the dark, stimulation of the contralateral eye or both eyes with bright light flashes (1-2 Hz) or with continuous light resulted in an increase in [K+]e of 0.5-1.0 mmol/l. Smaller increases in [K+]e of 0.15-1.25 mmol/l were found in HV and N after the application of a small quantity (0.1 ml) of the chemical taste aversant methylanthranilate (MeA) or the electrical stimulation of the beak by two needle electrodes inserted into the palatum or into the tongue. After application of MeA the increase in [K+]e began 3-4 min after application and persisted for 20 min.(ABSTRACT TRUNCATED AT 250 WORDS)
Animals↗
Humoral immune response to active root resorption with a murine model.
A depression in autoantibody titers to tooth root antigens has been shown to coincide with active root resorption in the dog. Since a murine model would facilitate immunologic studies of root resorption because of the availability of syngeneic and immunodeficient strains, the objectives of this study were to develop a quantitative mouse model for root resorption and to determine if a similar drop in tooth root autoantibodies coincides with active root resorption in this species. Uniform areas of necrosis were created in the periodontal ligaments of lower incisors of 36 male Swiss albino mice by inserting a cryoprobe through a skin incision (-80 degrees C; 5 minutes). Contralateral incisors served as controls. At 0, 3, 5, 7, 10, 14, and 21 days; six mice were killed, and blood and incisors were collected. Relative surface areas of root resorption were quantified with micrographs taken at a standardized position, tilt, and magnification with a scanning electron microscope. Serum autoantibody titers were determined with an enzyme-linked immune sorbent assay with antigen prepared from a 5 mol/L guanidine-HCl-EDTA (pH 5.0) extract of incisor roots that were harvested from syngeneic mice. ANOVA and the paired Student t test were used to compare data at the various time points. No root resorption was evident on control teeth. Localized lesions on treated teeth were found to be of significant size between 7 and 14 days (p less than 0.05), but most of these erupted into the mouth by 21 days.(ABSTRACT TRUNCATED AT 250 WORDS)
Animals↗
Hypercalcemia in squamous cell carcinoma of the head and neck.
In a consecutive series of 771 patients with pathologically verified squamous cell carcinoma of the head and neck, 28 patients (3.6%) had hypercalcemia (greater than 11.0 mg/dl) during the course of their disease. The buccal mucosa (16/205, 7.8%) and tongue (8/148, 5.4%) were the most frequent primary sites. Most of the patients were stage IV patients with recurrence and advanced disease. The prognosis was poor with a median survival of only 6 weeks. The possible etiology of their hypercalcemia included humoral factors, bone metastases and independent primary lung cancer. The treatment of hypercalcemia was evaluated in 22 patients. Success was noted in all patients initially receiving chemotherapy (10 cases) or radiotherapy (3 cases) with or without saline hydration plus furosemide diuretics. However, the response rate in patients (9 cases) initially receiving hydration plus furosemide diuretics alone was 22% (2/9), with 4 of 7 failure cases later responding to chemotherapy. It is suggested that hypercalcemia be treated with chemotherapy or radiotherapy quickly, along with hydration plus diuretics. Also, the serum calcium level must be checked in patients with advanced buccal or tongue cancer.
Adolescent↗
[Leiomyosarcoma associated hypoglycemia--report of two cases].
We report 2 cases of leiomyosarcoma associated hypoglycemia. Case 1 had had a tumor over his left thigh area for 13 years and a few episodes of hypoglycemia occurred when the tumor grew rather large (10 cm x 10 cm x 6 cm). Abdominal sonogram showed metastatic masses in the left lobe of liver. Hypoglycemia syndrome improved after chemotherapy, but relapse was noted later. Another case suffered from progressive abdominal distension for about one year and a huge mass (19 cm x 15 cm x 12 cm) over small intestine was found. Although surgical resection of the tumor and adjuvant chemotherapy was performed, recurrence of the tumor with hypoglycemia was noted. Both of the cases produced hypoglycemia in a fasting state rather than postprandial hypoglycemia. Hypoglycemia associated with non-islet cell tumor is one of the endocrinologic paraneoplastic Syndromes. The most common tumor found in this syndrome is sarcoma and such tumors are usually large when hypoglycemia is noted. Treatment of paraneoplastic hypoglycemia initially requires glucose infusion for acute symptomatic relief, then treatment of the underlying tumor. Reduction of tumor, radiotherapy or chemotherapy can improve the hypoglycemia syndrome, but it readily relapses.
Aged↗
Hepatocellular carcinoma presenting as bone metastasis.
In a consecutive series of 395 patients with pathologically verified hepatocellular carcinoma, 20 patients (5%) had bone metastasis at initial presentation. Of these, 16 were men and four women ranging from 26 to 64 years of age (median, 50 years). The age, sex, hepatitis B surface antigen seropositivity, alpha-fetoprotein level, and frequency of associated cirrhosis were not statistically different from those in patients without initial bone metastasis. Initial presentation was usually the result of spinal lesion with neurologic compression, and chest wall or scalp mass. Metastasis most commonly involved spine and ribs, and occurred as osteolytic lesions or extrapleural mass. Computed tomography proved best for demonstrating an expansile soft tissue mass with bony destruction. Angiography showed hypervascular appearance over the destructive bone area. Treatment results were poor. The follow-up period ranged from 3 weeks to 14 months with a median survival of 5 months. The data suggested that hepatocellular carcinoma be ruled out in patients with osteolytic lesions.
Adult↗
Memory formation processes in weakly reinforced learning.
Day-old chicks trained on a single-trail passive avoidance learning task, with varying concentrations of the aversive stimulus (methyl anthranilate), truncated retention functions for low concentrations. The retention function for a 20% v/v dilution of methyl anthranilate in absolute ethanol yielded high retention levels until approximately 40 to 45 minutes following learning. This retention function appears to consist of only the short-term and intermediate (phase A) memory stages of Gibbs and Ng's three-stage model of memory formation, with the short-term stage susceptible to inhibition by monosodium glutamate, and the intermediate stage by ouabain and dinitrophenol. The results suggest that processing of memory into the relatively permanent long-term stage may depend on the strength of the reinforcer in aversive learning.
2,4-Dinitrophenol↗
Effect of retraining trials on memory consolidation in weakly reinforced learning.
Day-old chicks given a single weakly reinforced (20% v/v methyl anthranilate in absolute ethanol) passive avoidance learning trial showed no evidence of long-term memory. A second learning trial given at 15 minutes after initial resulted in consolidation of the learning experience into long-term memory. The retention function resulting from two learning trials is similar to that observed with a single strongly reinforced learning trial, and consists of the stages postulated by Gibbs and Ng. With a dilution of 10% methyl anthranilate in ethanol, four training trials were needed to yield unequivocal evidence of long-term memory consolidation.
2,4-Dinitrophenol↗
Automated capillary gas chromatographic assay using flame ionization detection for the determination of topiramate in plasma.
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Animals↗
Symptomatic pericardial effusion in cancer patients.
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Adolescent↗