Search PubMed⌕ Search

Biomedical subjects

G Lynch

Publications and source records attributed to G Lynch.

At least 235 records · Page 13Linked to original sources
PubMed1994

Kainate binding to the AMPA receptor in rat brain.

Displacement of [3H]AMPA and [3H]CNQX by kainate was measured in membranes and solubilized fractions from rat brain. In soluble fractions, plots of [3H]AMPA and [3H]CNQX binding displaced by kainate resulted in one-site fits with Ki values in the range of 1-3 microM. In membranes, plots of [3H]AMPA binding displaced by kainate resulted in graphs which were better fit by two-site regression analysis than by a one-site fit. The Ki value for the high-affinity component of these two-site fits was 3-9 microM and the low-affinity component Ki was in the range of 70-120 microM; similar values were determined for kainate displacement of [3H]CNQX. The presence of thiocyanate ions had no effect on kainate displacement of [3H]CNQX. Since the affinity for kainate of the presumed synaptic AMPA receptor is in the range of EC50 values for kainate determined from physiological studies, these data contribute further evidence for the idea that kainate binding to synaptic AMPA receptors may be responsible for many of kainate's physiological effects.

6-Cyano-7-nitroquinoxaline-2,3-dione↗
PubMed1994

Treatment with coumarin to prevent or delay recurrence of malignant melanoma.

Both coumarin (1,2-benzopyrone) and warfarin (4-hydroxycoumarin) have been shown to prevent the recurrence of malignant melanoma. Their action is macrophage-dependent and the dosage is critical. In 1984 a multicentre, prospective, randomised, double-blind trial of coumarin, given as a daily 50-mg dose for 2 years after surgery in patients with high-risk melanoma, was started. the patients had lesions greater than 1.70 mm thick and TNM stage IB or stage II disease. To date there are 4 recurrences in the coumarin-treated group of 13 patients, and 10 recurrences in the placebo-treated group of 14 patients (P < 0.01). There were no toxic effects.

Chemotherapy, Adjuvant↗
PubMed1994

Rapid and stable gene expression in hippocampal slice cultures from a defective HSV-1 vector.

Stable transfer of genetic information into neurons is a powerful strategy to elucidate specific mechanisms of neurophysiology and to develop therapies for neurological disorders. To evaluate the optimal parameters for efficient gene delivery of defective herpes simplex virus type one (HSV-1) vectors into a specific brain region, an HSV-1 vector expressing E. coli beta-galactosidase was used to infect organotypic cultures of hippocampal slices. beta-Galactosidase was expressed as early as 2 h after infection in a dose-dependent manner as measured on immunoblots, and reached a maximum level after approximately 35 h. Expression of the RNA and the antigen was still evident after the longest time sampled (11-12 days), whereas no beta-galactosidase was ever detected in cultured slices infected with a control virus lacking the reporter gene. Hippocampal cells expressing the reporter gene outlined the contour of the neuronal cell body layers in fields CA3 and dentate gyrus; such correspondence was less evident in field CA1. Anatomical, morphological, and immunohistochemical criteria also confirmed that the majority of these infected cells were neurons. beta-Galactosidase was also detected in the somata and processes of infected interneurons. Tests for synaptic pathology associated with virus infection showed no changes in pre- and postsynaptic markers.

Animals↗
PubMed1994

Use of chromosome microdissection, the polymerase chain reaction, and dot blot hybridization to analyze double minute chromosomes.

The potential usefulness of chromosome microdissection, the polymerase chain reaction (PCR), and dot blot hybridization as a quick screening method for determining the genetic composition of double minute chromosomes (DMs) was evaluated. DMs or abnormally banding regions (ABRs) were microdissected from multidrug-resistant hamster cell lines and amplified with PCR using primers specific for the hamster multidrug-resistance (MDR) gene, pgp 1. The microdissected-PCR-amplified products were shown to (a) hybridize to a 32P-labeled pCHP1 probe for the hamster MDR gene by using dot blot or Southern blot analysis and also (b) hybridize back to the chromosome region from which they were originally dissected by using fluorescent in situ hybridization. Microdissected/PCR-amplified DMs were also shown to hybridize to ABRs. When microdissected DMs and ABRs were amplified using hamster specific Alu primers, the resulting material was shown to hybridize with probes for hamster MDR and Alu. These results suggest that the DMs contained in these MDR hamster cell lines contain Alu-like sequences and the chromosome microdissection-PCR-hybridization approach might be used as a quick screening method for identifying genes amplified in DMs and ABRs in cell lines and human tumor samples.

Animals↗
PubMed1994

Does the wearing of sampling pumps affect exposure?

There is a possibility that wearing traditional sampling pumps could affect worker behaviour and undermine the validity of occupational hygiene exposure measurement. Sampling pumps are bulky and can be noisy, and if these characteristics alter work patterns sufficiently exposures may be modified. This paper describes a carefully controlled pilot study designed to test the hypothesis that the wearing of personal sampling pumps may affect workers' exposure. Comparisons were made using pump-based systems and diffusive samplers to measure organic vapours. Diffusive samplers were chosen as controls because they are much less bulky and therefore less likely to affect behaviour. A carefully constructed sampling strategy, involving measurements on between 13 and 20 workers on 6 working days, was used at five sites. On alternate days both sampling methods were used, side-by-side, on the workers and on the remaining days only diffusive samplers were worn. The sites chosen had minimal day-to-day variation in environmental conditions. The results showed that at one site the concentrations were approximately 50% higher on the days when pumps were worn compared with other days. At the remaining sites no significant differences were found. From the characteristics of the work at the site where differences were observed it is suggested that pumps may affect measured concentrations when people have flexible work patterns and spend part of their time seated and/or the work is in quiet areas.

Bias↗
PubMed1994

Malignant cystosarcoma phyllodes.

UNLABELLED: This study reviewed 26 women who had resection of a malignant cystosarcoma phyllodes. Clinical presentations were palpable mass, 25; pain, 11; and ulceration, 2. Definitive surgical therapy was radical mastectomy (RM), 2; modified radical mastectomy (MRM), 14; total mastectomy (TM), 4; and partial mastectomy (PM), 6. Tumors ranged in size from 1-20 cm (median, 7 cm). Eight patients developed recurrent disease after 10-45 months. Local recurrence was more likely after TM and PM than after MRM and RM (P < 0.05). Patients who developed local recurrence only were treated by wide re-excision, and all such patients are alive with no evidence of disease at 5-25 years. Only one of 16 patients undergoing axillary dissection had involved lymph nodes. Four patients whose tumors ranged from 5-8 cm and who underwent one RM and three MRM developed systemic recurrence; all died of their disease after 15-48 months. CONCLUSION: 1) Although there is a higher local recurrence after PM and TM as compared with MRM and RM for malignant cystosarcoma phyllodes, the local recurrence can be treated with wide excision without affecting long-term survival; 2) systemic recurrence was not related to size or extent of resection; 3) axillary dissection does not predict for or prevent recurrence.

Adult↗
PubMed1993

Simulated dendritic spines influence reciprocal synaptic strengths and lateral inhibition in the olfactory bulb.

Whereas many theories have been proposed for the function of dendritic spines in axodendritic processing, the influence of spines on reciprocal dendrodendritic processing has received relatively little attention. Mitral cells in the olfactory bulb, for example, synapse on granule cell spines (gemmules) which are in turn presynaptic to reciprocal inhibitory synapses back onto the same mitral cells. The postulate that these synapses respond with synaptic strengths graded by presynaptic depolarization results in a sensitivity of the reciprocal response to the local depolarization in the spine head. A biophysical computer simulation was performed to study this effect and the effect of changing the spine neck diameter and cytoplasmic resistance on the reciprocal and lateral inhibitory responses given graded dendrodendritic synapses. Since spine head local potentials are larger than similar inputs on dendritic shafts, spines facilitate the graded reciprocal response even for low levels of activity. Spine heads also reduce the synaptic current, lowering the contribution to the rest of the granule dendritic tree and thus reducing lateral inhibition. In addition, an increase in the effective spine neck axial resistance further increases the reciprocal synaptic response and decreases the lateral inhibitory response. Short-term, reversible, and long-term methods of implementing this resistance-based dendrodendritic plasticity are discussed as well as the partial dependence of the reciprocal increase/lateral decrease effect on a broad synaptic gradation. Candidate memory operations by the bulb are also discussed, including a possible recognition memory pass/block function.

Computer Simulation↗
PubMed1993

Age-related changes in neural cell adhesion molecule (NCAM) isoforms in the mouse telencephalon.

The concentrations of different polypeptide isoforms of the neural cell adhesion molecule NCAM were examined in telencephalic and brainstem-cerebellar tissue from groups of young (3 months) and old (25 months) mice. Antibodies against chick brain NCAM were used in immunoblot analyses to quantify 180 (NCAM180) and 140 (NCAM140) kDa NCAM forms in mouse brain samples containing equal amounts of protein. Telencephalic homogenates from the older group exhibited 37% and 31% less NCAM180 and NCAM140 immunoreactivity, respectively, when compared with homogenates from the younger animals. Brainstem-cerebellar homogenates, however, did not express such age-related changes in the two NCAM isoforms. Age-related changes in isoforms labeled by the anti-NCAM antibodies were not evident in synaptic plasma membranes. NCAM180:NCAM140 ratios were 2- to 3-fold greater in the synaptic membranes vs. homogenates for both age groups. These data suggest that expression levels of NCAM180 and NCAM140 are selectively impaired with aging in the telencephalon, whereas the synaptic contents of these molecules appear to be stably regulated.

Aging↗
PubMed1993

Cyclothiazide decreases [3H]AMPA binding to rat brain membranes: evidence that AMPA receptor desensitization increases agonist affinity.

The effects of cyclothiazide, a drug which blocks AMPA (alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid) receptor desensitization, were tested on binding of [3H]AMPA to rat brain membranes. Cyclothiazide reduced [3H]AMPA binding by lowering the apparent affinity of the AMPA receptor. The magnitude of the decrease was temperature dependent and greater for membrane-bound than for solubilized receptors. These data provide evidence that desensitization increases the affinity of the AMPA receptor for agonists and indicate that a significant percentage of AMPA receptors in conventional equilibrium binding assays are in a desensitized state.

Animals↗
PubMed1993

Waveform analysis suggests that LTP alters the kinetics of synaptic receptor channels.

The waveform of an isolated excitatory monosynaptic response reflects the kinetics of transmitter release, the kinetics of synaptic receptor channels and the filtering properties of neurons. Results reported here indicate that long-term potentiation (LTP) causes correlated decreases in the rise time and decay time constant of synaptic potentials recorded in hippocampal slices in which inhibitory currents and post-synaptic spiking were suppressed. Statistical comparisons of waveforms revealed that the distortions introduced by LTP could be corrected by stretching the time-scale of potentiated responses according to the percent change in the decay time constant. The LTP associated decrease in the decay time constant also obtained in slices from immature hippocampus which contain spines and dendrites greatly simplified from those of the adult. Hence, filtering properties of spines are not likely involved in the effect. Paired-pulse facilitation (PPF), a transient increase in transmitter release, did not reproduce the waveform effects of LTP but did cause a slight leftward shift of the response. These results suggest that LTP modifies the kinetics of receptor channels, and that PPF accelerates release.

Animals↗
PubMed1993

Channel gating kinetics and synaptic efficacy: a hypothesis for expression of long-term potentiation.

A kinetic model of the glutamate DL-alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor/channel complex was used to test whether changes in the rate constants describing channel behavior could account for various features of long-term potentiation (LTP). Starting values for the kinetic parameters were set to satisfy experimental data (e.g., affinity, mean open time, mean burst length, etc.) and physical constraints (i.e., microreversibility). The resultant model exhibited a variety of dynamic properties known to be associated with the receptor. Increasing the rate constants governing opening/closing of the channel produced an unexpected increase in the probability of the channel being open shortly after transmitter binding. This would account for the enhanced response size with LTP. Increases in rate constants produced two other aspects of LTP: (i) an alteration of the waveform of the synaptic response and (ii) an interaction with changes in desensitization kinetics. The results obtained with the model corresponded closely to those found in LTP experiments. Thus, an increase in opening/closing rates for the postsynaptic receptor channel provides a single explanation for diverse characteristics of LTP. Finally, the kinetic manipulation reduced the coefficient of variation of synaptic currents in a model involving 250 receptors. This calls into question the use of variance measures for distinguishing pre- vs. postsynaptic sites of potentiation.

Animals↗
PubMed1993

Single channel recordings of reconstituted AMPA receptors reveal low and high conductance states.

Glutamate receptors belonging to the AMPA (alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid) subclass were partially purified 30- to 60-fold from forebrain of adult rats and incorporated into planar bimolecular lipid membranes. The channel conductance associated with the reconstituted receptors was activated by kainate and AMPA in a manner that suggests cooperative binding of two to three agonist molecules is required to induce channel opening. This conductance was blocked by the specific antagonist DNQX (6,7-dinitroquinoxaline-2,3-dione). When the partially purified AMPA receptors were reconstituted by the tip-dipping method in asymmetric saline conditions ('outside-out configuration'), the addition of 300 nM AMPA to the pseudo-extracellular solution elicited single channel current fluctuations that were also inhibited by DNQX. Analyses of the currents revealed that the ion channels of reconstituted AMPA receptors have two distinct conductance levels of 12 and 60 pS with the great majority of receptors belonging to the former variety. These results suggest that reconstitution may be useful in identifying factors that regulate the binding and conductance properties of AMPA receptors.

Animals↗
PubMed1993

Reversal of LTP by theta frequency stimulation.

Reversal of long-term potentiation (LTP) by physiological stimulation was tested in the CA1 field of hippocampal slices. In control medium, a one minute episode of 5 Hz (theta frequency) stimulation beginning 1-3 min after LTP had no effect on the degree of potentiation measured 30 min later. However, in the presence of norepinephrine (200 microM), 5 Hz stimulation reduced LTP by about 30%. Theta frequency stimulation was only effective when administered within 10 min of LTP induction and had no lasting effects on non-potentiated synapses. Stimulation at 1 Hz did not reverse LTP and stimulation at 10 Hz was no more effective than 5 Hz stimulation. LTP could be nearly completely reversed by theta frequency stimulation when potentiation was induced by milder and more naturalistic stimulation patterns. Under these conditions, LTP reversal was blocked by an antagonist of adenosine A1 receptors. These results suggest that the hippocampal theta rhythm promotes both the induction of LTP and its subsequent reversal with the latter process involving activation of adenosine receptors. Reversal of LTP may function to refine or sharpen recently encoded representations.

Animals↗
PubMed1993

A drug that facilitates glutamatergic transmission reduces exploratory activity and improves performance in a learning-dependent task.

A recently developed benzamide compound which facilitates glutamate receptor-mediated synaptic responses was used to test behavioral consequences of enhanced glutamatergic transmission. The drug was found to depress exploratory activity by rats in a novel environment. At a dose below threshold for causing such effects, drug-treated and control rats exhibited no evident behavioral differences during the acquisition phase of a radial maze experiment. Yet, when tested 2.5 h later, experimental animals were more likely than controls to choose maze arms that had not been entered during the acquisition session, suggesting that the drug enhanced retention of information about prior choices and the maze environment.

Animals↗
PubMed1993

Post traumatic intussusception in an adult.

Intussusception is a rare cause of intestinal obstruction in adults. When seen most cases have identifiable pathology. Intussusception following blunt abdominal trauma is extremely rare. This report presents a case of double jejuno-jejunal intussusception in a patient who sustained such an injury. There was no other intra-abdominal abnormality and manual reduction resulted in a complete recovery. The coincidental discovery of Q-fever may be etiologically relevant.

Abdominal Injuries↗
PubMed1993

Intralesional interferon-alpha and zidovudine in epidemic Kaposi's sarcoma.

BACKGROUND: Kaposi's sarcoma (KS) is the most common neoplasm in patients with acquired immunodeficiency syndrome (AIDS). To date, no therapy has proved to be consistently effective. OBJECTIVE: The purpose of this study was to evaluate the efficacy of intralesional interferon-alpha in patients with epidemic KS who were taking zidovudine. METHODS: Up to five lesions in each of 14 patients entered into the study were injected with 1 million U of interferon-alpha three times weekly for 6 weeks. Sterile water was used as a placebo control. The median zidovudine dose was 500 mg/day. The median CD4 count was 23/microliters. RESULTS: Of 14 patients evaluated, 13 of 14 (93%) showed a clinical complete response (CR) or partial response (PR) to therapy. Of 54 lesions injected, 41 (76%) showed a CR and 5 (9%) showed a PR, which resulted in an overall response rate of 85%. CONCLUSION: Intralesional interferon-alpha produced a high response rate in injected lesions of KS, but it failed to demonstrate superior efficacy over the placebo.

Acquired Immunodeficiency Syndrome↗
PubMed1993

Corticosterone exacerbates kainate-induced alterations in hippocampal tau immunoreactivity and spectrin proteolysis in vivo.

Aberrant elevations in intracellular calcium levels, promoted by the excitatory amino acid glutamate, may be a final common mediator of the neuronal damage that occurs in hypoxic-ischemic and seizure disorders. Glutamate and altered neuronal calcium homeostasis have also been proposed to play roles in more chronic neurodegenerative disorders, including Alzheimer's disease. Any extrinsic factors that may augment calcium levels during such disorders may significantly exacerbate the resulting damage. Glucocorticoids (GCs), the adrenal steroid hormones released during stress, may represent one such extrinsic factor. GCs can exacerbate hippocampal damage induced by excitotoxic seizures and hypoxia-ischemia, and we have observed recently that GCs elevate intracellular calcium levels in hippocampal neurons. We now report that the excitotoxin kainic acid (KA) can elicit antigenic changes in the microtubule-associated protein tau similar to those seen in the neurofibrillary tangles of Alzheimer's disease. KA induced a transient increase in the immunoreactivity of hippocampal CA3 neurons towards antibodies that recognize aberrant forms of tau (5E2 and Alz-50). The tau immunoreactivity appeared within 3 h of KA injection, preceded extensive neuronal damage, and subsequently disappeared as neurons degenerated. KA also caused spectrin breakdown, indicating the involvement of calcium-dependent proteases. Physiological concentrations of corticosterone (the species-typical GC of rats) enhanced the neuronal damage induced by KA and, critically, enhanced the intensity of tau immunoreactivity and spectrin breakdown. Moreover, the GC enhancement of spectrin proteolysis was prevented by energy supplementation, supporting the hypothesis that GC disruption of calcium homeostasis in the hippocampus is energetic in nature. Taken together, these findings demonstrate that neurofibrillary tangle-like alterations in tau, and spectrin breakdown, can be induced by excitatory amino acids and exacerbated by GCs in vivo.

Animals↗