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Biomedical subjects

A Williamson

Publications and source records attributed to A Williamson.

At least 19 recordsLinked to original sources
PubMed1995

Zinc reduces dentate granule cell hyperexcitability in epileptic humans.

The hippocampi of epileptic patients with medial temporal lobe epilepsy exhibit a characteristic pattern of anatomical changes including cell loss and sprouting of the granule cell axons, the mossy fibers, into the inner molecular layer of the dentate. In addition to glutamate, mossy fibers release Zn2+. In the present study we investigated the action of Zn2+ on excitatory synaptic potentials in the dentate granule cells of patients with medial temporal lobe epilepsy. We show here that Zn2+ limits the duration of excitatory responses in these cells, probably by blocking the N-methyl-D-aspartate (NMDA) receptors. Zinc may, therefore, play an important role in limiting epileptiform activity in this issue.

2-Amino-5-phosphonovalerate↗
PubMed1995

Depth electrode studies and intracellular dentate granule cell recordings in temporal lobe epilepsy.

Hippocampal depth electrodes are often used to localize seizure onset in patients who may have temporal lobe epilepsy (TLE). A number of features of the spontaneous seizures and of their ictal onset patterns can be analyzed from these recordings. We compared a number of the typical electroencephalographic (EEG) changes at seizure onset with several cellular parameters recorded in dentate granule cells from the same 14 patients diagnosed with medial temporal sclerosis (MTS) to examine the pathophysiological correlates of this spontaneous EEG activity in this form of TLE. The intracellularly recorded parameters include the propensity to fire evoked epileptiform bursts, the absence of evoked inhibitory potentials, the presence of polysynaptic excitatory postsynaptic potentials, and the presence of spontaneous excitatory activity. We noted several correlations between the EEG data and the intracellular recordings. The absence of synaptically evoked bursts was correlated with the presence of low-voltage fast activity at seizure onset. In addition, the loss of inhibitory postsynaptic potentials was correlated with the presence of periodic spiking pre-ictally. Several other correlations were also noted. These data indicate that EEG findings may be predictive of anatomical and cellular pathological changes and provide clues to the physiological mechanisms involved in this form of epilepsy.

Action Potentials↗
PubMed1995

Prolonged GABA responses in dentate granule cells in slices isolated from patients with temporal lobe sclerosis.

1. Medial temporal lobe sclerosis is a common pathological finding in patients with medically intractable temporal lobe epilepsy. This disease is characterized by extensive cell loss in the hilus and the hippocampal CA1 and CA3 cell fields in addition to synaptic reorganization throughout the dentate gyrus. 2. The dentate granule cells from hippocampal slices of patients diagnosed with medial temporal lobe sclerosis exhibit reduced synaptic inhibition with concommitant hyperexcitability. These physiological changes were studied relative to the hippocampi of patients with temporal lobe tumors in which the cell loss and synaptic reorganization are not seen. 3. We attempted to determine if this disinhibition was because of changes in the postsynaptic sensitivity to the inhibitory neurotransmitter gamma-aminobutyric acid (GABA) by studying the responses to exogenously applied transmitter. As in rodents, the GABA responses in human dentate granule cells studied at the resting membrane potential were depolarizing and were mediated primarily by GABAA receptors. In many cases, these depolarizing GABA responses could trigger action potentials. Thus in some situations, GABA could act as an excitatory neurotransmitter. 4. We found that GABAA receptor-mediated responses in the sclerotic hippocampi were approximately 80% longer than in the comparison population. This difference was not because of changes in either the GABA reversal potential or the GABA-induced conductance change. The data support the hypothesis that the GABA transport system is impaired in sclerotic tissue: application of the GABA uptake inhibitor NNC711 (a tiagibine derivative) greatly prolonged the GABA responses in the tumor-related temporal lobe epilepsy tissue, but had little effect on the sclerotic tissue.

Action Potentials↗
PubMed1995

Relationship between synaptic activity and prolonged field bursts in the dentate gyrus of the rat hippocampal slice.

1. Previous studies in the dentate granule cell layer of the rat hippocampal slice have demonstrated that nonsynaptic, seizurelike prolonged field bursts occur in conditions of low extracellular Ca2+ concentration ([Ca2+]o) and elevated [K+]o. We hypothesize that the extracellular ion concentration changes induced by synaptic activation of dentate granule cells would be sufficient to initiate these nonsynaptic bursts. 2. Using ion-selective electrode recording, we observed large changes in [Ca2+]o (from 1.3 mM baseline to approximately 0.7 mM) and [K+]o (from 3.5 to approximately 12 mM) in the dentate granule cell layer during repetitive electrical stimulation of the perforant path in rat hippocampal slices. Concomitant with these changes, bursts of population spikes similar to those seen during spontaneous prolonged field bursts appeared between the individual stimulus-evoked responses in the dentate gyrus in many of the slices studied (19 of 27). 3. Blockade of N-methyl-D-aspartate (NMDA), non-NMDA, and gamma-aminobutyric acid-A (GABAA)-mediated synaptic transmission during perforant path stimulation resulted in a marked reduction of the ion concentration changes and a loss of both stimulus-evoked and stimulus-independent population spikes in the dentate gyrus. 4. When slices were perfused with solutions containing [Ca2+]o and [K+]o equivalent to those measured during perforant path stimulation (i.e., 0.7 and 12 mM, respectively), spontaneous prolonged field bursts appeared in the dentate gyrus. Addition of NMDA, non-NMDA, and GABAA receptor antagonists did not prevent the occurrence of these spontaneous bursts. 5. We conclude that changes in [Ca2+]o and [K+]o sufficient to produce prolonged field bursts may be created in the dentate granule cell layer by perforant path stimulation. These effects are dependent on synaptic transmission. Once these ionic conditions occur, they are sufficient to trigger prolonged field bursts independent of fast amino-acid-mediated synaptic transmission. A similar mechanism could be important during the interictal-ictal transition in vivo.

Animals↗
PubMed1994

Electrophysiological characterization of CA2 pyramidal cells from epileptic humans.

The CA2 region of the hippocampus is more resistant to the principal cell loss seen in CA1 and CA3 in both animal models of temporal lobe epilepsy and in medial temporal lobe sclerosis (MTS), a common neuropathological finding in human temporal lobe epilepsy. There is extensive synaptic reorganization in the MTS hippocampi that is not seen in the hippocampi of patients with tumor-associated temporal lobe epilepsy (TTLE). The authors examined the electrophysiological properties of CA2 pyramidal cells from these two types of human hippocampi. The two main findings are that most MTS cells do not have clear evidence for inhibition yet do not fire synaptically evoked bursts; and that mossy fiber stimulation could evoke excitatory postsynaptic potentials (EPSPs) in the MTS tissue, but not the TTLE cells. These data suggest that in MTS, CA2 cells are resistant to firing epileptiform bursts which may account for their survival. Moreover, the granule cell-CA2 cell connection represents a novel form of synaptic plasticity in this disease.

Animals↗
PubMed1993

Comparison between the membrane and synaptic properties of human and rodent dentate granule cells.

We have compared the cellular and synaptic properties of rodent dentate granule cells with those of humans. The human tissue was obtained from neurosurgical procedures which necessitated removal of the hippocampus for treatment of extra-hippocampal tumors which presented clinically with seizures. The hippocampi studied here were neuroanatomically similar to autopsy controls. The present studies have demonstrated that there are few differences between rodent and human granule cells as regards either their membrane properties or their synaptic physiology and pharmacology. The differences we noted were (1) less spike frequency adaptation in the human relative to rodent cells; and (2) perforant path stimulation reliably elicited both feedforward and feedback inhibition in the rodent cells, while in the human tissue feedback inhibition appeared to predominate. It is unclear if these changes are due to the seizure experience or if they represent true species differences.

Action Potentials↗
PubMed1992

Driving in Alzheimer's disease.

OBJECTIVE: To determine if the impaired mental skills in Alzheimer's Disease (AD) may adversely affect driving ability. DESIGN: Retrospective survey. SETTING: The Alzheimer's Clinic of the University of Kansas Medical Center. PATIENTS: We interviewed 67 AD patients and their families and compared them with 100 elderly, non-spousal controls. MEASURES: The questionnaire was designed to obtain information on their driving habits, with emphasis placed on whether they were still driving, and the number of accidents per year for the past 10 years. RESULTS: Forty-six of the AD subjects had stopped driving because of safety concerns expressed by the subjects, their families, or health care providers, and two had stopped for other reasons. Only two of the normal controls had stopped driving (P < 0.0001, Chi-square test). Over the past 3 years, the 19 AD subjects who were still driving had 263.2 motor vehicle accidents per million vehicle miles of travel compared with 14.3 for the controls (P < 0.002, Mann-Whitney U test) and 5.7 for the general driving population age > or = 55 years (P < 0.05, Students one group, two-tailed t test). CONCLUSION: This study suggests that a significant traffic safety problem exists in subjects with AD who continue to drive. Efforts should be directed to detect patients with AD whose driving presents a traffic safety problem.

Accidents, Traffic↗
PubMed1992

Role of psychosocial risk factors in work-related low-back pain.

The experience of low-back pain and its psychosocial associates were directly compared among sufferers drawn from three populations, a blue-collar working group, a white-collar working group, and a patient group. Sufferers drawn from the patient population revealed the expected psychological disturbance. There was no evidence of such involvement for sufferers still at work. Disability resulting from low-back pain was positively linearly related to severity of pain for sufferers drawn from working groups, irrespective of psychological disturbance. For patients, on the other hand, the presence of psychological disturbance modified the relationship between severity and disability such that no simple linear relationship existed between the two variables. Work dissatisfaction was not found to be related to the presence of, and did not account for disability resulting from, low-back pain in working subjects.

Adult↗
PubMed1992

Neurotransmitters and their receptors in human temporal lobe epilepsy.

Patients with medically intractable temporal lobe epilepsy (TLE) undergo medial temporal lobectomy with hippocampectomy for one of two reasons. (1) A lesion (tumor or arteriovenous malformation) adjacent to, but not invasive of, the hippocampus, results in the removal of the lesion and adjacent hippocampus in order to ensure a tumor-free margin. This group will be referred to as tumor-related TLE (TTLE) patients. (2) The operation is performed when depth electrode recordings and other evaluative techniques point to the hippocampus as the focus of seizure initiation. This group will be referred to as cryptogenic TLE (CTLE) patients. Analysis of the hippocampi of these two groups of patients reveals that the TTLE hippocampus is quite similar to that of autopsy subjects in its chemical neuroanatomy. However, the dentate gyrus of the CTLE patients shows considerable morphological and cytochemical reorganization. This reorganization is characterized by a number of features. (1) There is a loss of granule cells which occurs either as a patchy loss and/or a thinning of the granule cell layer. (2) Remaining granule cells which contain dynorphin appear to produce recurrent collaterals into the inner molecular layer of the dentate gyrus. (3) In the subgranular region of the hilus (the polymorphic layer) there is a selective loss of interneurons immunoreactive for somatostatin, neuropeptide Y and substance P. (4) There appears to be an increase in fibers immunoreactive for somatostatin and neuropeptide Y which extend throughout the dentate molecular layer. Somatostatin fibers being less numerous than neuropeptide Y fibers (5). The distributions of a number of neurotransmitter receptors also show striking reorganization in the dentate gyrus of the CTLE hippocampus. (6) Second messenger systems protein kinase C and adenylate cyclase, and Na+, K(+)-ATPase activity, as determined by ouabain binding, is increased in the molecular layer of CTLE. This remodeling of the CTLE hippocampus may hold the key to the mechanisms of hyperexcitability of the granule cells in the hippocampus of this group, and consequently the generation of seizures. The removal of the hippocampus in CTLE patients results in good control of seizures, whereas removal of hippocampi that do not show such reorganization, in a group of patients classified as atypical CTLE patients, results in inadequate seizure control. These findings suggest a complex series of processes in converting the properly regulated granule cells into hyperexcitable ones.

Afferent Pathways↗
PubMed1991

Endogenously synthesized peptide with an endoplasmic reticulum signal sequence sensitizes antigen processing mutant cells to class I-restricted cell-mediated lysis.

The HLA-A2-positive human mutant cell line T2 is not lysed by influenza virus-specific HLA-A2-restricted cytotoxic lymphocytes after virus infection. However, lysis does occur when cells are incubated with the antigenic influenza matrix protein-derived peptide M57-68. To examine the nature of this defect, T2 cells were transfected with two different plasmids. One plasmid encoded the peptide M57-68, and the other encoded the same peptide preceded by an endoplasmic reticulum translocation signal sequence. Mutant T2 cells expressing the M57-68 peptide without the signal sequence were not susceptible to lysis by M57-68-specific HLA-A2-restricted cytotoxic T lymphocytes, whereas T2 cells expressing the M57-68 peptide plus signal sequence were lysed effectively. Lysis of parental T1 cells with either plasmid was equally effective. These results suggest that the T2 mutant cells are defective in the transport of antigenic peptides from the cytosol into the secretory pathway.

Amino Acid Sequence↗
PubMed1991

Actions of norepinephrine in the cerebral cortex and thalamus: implications for function of the central noradrenergic system.

Norepinephrine (NE) has potent and long-lasting ionic effects on cortical and thalamic neurons. In cortical pyramidal cells, activation of beta-adrenergic receptors results in an enhanced excitability and responsiveness to depolarizing inputs. This enhanced excitability is expressed as a reduction in spike frequency adaptation and is mediated by a marked suppression of a slow Ca(++)-activated potassium current known as IAHP. In the thalamus, application of NE results in the suppression of ongoing rhythmic burst activity and a switch to the single spike firing mode of action potential generation. This effect is mediated through an alpha 1-adrenergic suppression of a resting leak potassium current, IKL, and through a beta-adrenoceptor-mediated enhancement of the hyperpolarization activated cation current Ih. Together with the actions of other neuromodulatory neurotransmitters (i.e., acetylcholine, histamine, serotonin) these effects facilitate the switch of these neurons from a state of rhythmic oscillation and low excitability during drowsiness and slow-wave sleep to a state of increased excitability and responsiveness during periods of waking, attentiveness and cognition.

Action Potentials↗
PubMed1991

Modulation of neuronal firing mode in cat and guinea pig LGNd by histamine: possible cellular mechanisms of histaminergic control of arousal.

The thalamus is innervated by histaminergic fibers presumably arising from neurons in the tuberomammillary nucleus of the hypothalamus. The possible function of this histaminergic projection was addressed through investigation of the cellular actions of histamine on guinea pig and cat dorsal lateral geniculate (LGNd) relay neurons maintained as a slice in vitro. Local application of histamine to LGNd relay neurons resulted in a slow depolarization that was associated with a decrease in membrane conductance and was blocked by the H1-antagonists pyrilamine, triprolidine, or diphenhydramine. Current versus voltage relationships revealed that the slow depolarization was associated with an inward current that reversed near EK, indicating that it was due to a decrease in a potassium current. The slow depolarizing response to histamine was occluded by maximal activation of the slow depolarizing responses resulting from stimulation of alpha 1-adrenergic or muscarinic receptors, suggesting that they are all mediated by reduction in the same potassium current and/or alteration of a common second messenger. In the presence of H1-receptor antagonists, application of histamine resulted in a small depolarization that was associated with a marked increase in apparent membrane conductance. Voltage-clamp recordings revealed that this response was associated with enhancement of the hyperpolarization-activated cation current Ih. This response to histamine was blocked by local or bath application of the H2-antagonists cimetidine or tiotidine. The functional consequences of these actions of histamine were addressed with extracellular and intracellular recordings in guinea pig and cat LGNd relay neurons. Extracellular recordings in cat LGNd revealed the occurrence of highly regular 1-4 Hz rhythmic burst discharges. Application of histamine halted rhythmic bursting and replaced it with a prolonged period of single-spike activity. Intracellular recordings indicate that the histamine-induced switch in firing mode is due largely to the slow depolarizing response mediated by H1-receptors, but is also facilitated by the enhancement of Ih mediated by H2-receptors. These postsynaptic actions indicate that increased activity in the tuberomammillary histaminergic system may result in a switch of thalamic neuronal activity from rhythmic burst firing to single-spike activity and thereby promote the accurate transmission and processing of sensory information and cognition.

Acetylcholine↗
PubMed1991

Aortic counterpulsation for up to 28 days with autologous latissimus dorsi in sheep.

This article reports the development and assessment of an entirely autologous extraaortic counterpulsation system using skeletal muscle (latissimus dorsi). The technique has been performed and assessed in 16 sheep to quantify the effectiveness of counterpulsation over periods up to 28 days and to optimize the stimulation regimens for muscle contraction and fiber-type transformation. Hemodynamic changes have been quantified by calculation of the endocardial viability ratio. This has shown an increase of between 12% and 89% for 28 days. The wide variety of increase observed has been related to the development of an optimum flap configuration. The technique of surface impedance monitoring of flap blood flow has allowed the start of electrical stimulation after 48 hours with the introduction of hemodynamic benefit (1:4 mode) during the process of fiber-type transformation (in situ training). Extraaortic counterpulsation with autologous latissimus dorsi has been shown to be effective and safe for as long as 28 days. It has not been associated with any thromboembolic or infective complications, which we attribute to the exclusion of any foreign material in the design.

Animals↗
PubMed1991

The management of otitis media with effusion.

Otitis media with effusion is one of the most common otologic diseases encountered by the clinician. This is primarily a pediatric problem although it can be seen in all age groups. The etiology, diagnosis, and treatment of this disorder will be discussed in this manuscript.

Humans↗
PubMed1990

A prolonged post-tetanic hyperpolarization in rat hippocampal pyramidal cells in vitro.

The post-tetanic sequelae of trains of synaptic stimuli (50 pulses at 5 or 10 Hz) were studied with intracellular recordings from rat hippocampal neurons in vitro. In a large proportion of CA1 neurons, stimulation of afferent fibers was followed by a prolonged membrane hyperpolarization (peak amplitude approximately 6 mV) that was associated with a decrease in neuronal input resistance (approximately 33%) that lasted from tens of seconds to over 1 min. Antidromic stimulation or activation of cells with intracellular current injection did not elicit this post-tetanic hyperpolarization (PTH). The PTH could be elicited in chloride (Cl-)-loaded cells, its null potential shifted in response to changes in extracellular potassium ([K+]o), and it was significantly reduced by 5-10 mM extracellular cesium (Cs+). The K(+)-dependent PTH may also be calcium (Ca2+) dependent as its amplitude and associated conductance increase were sensitive to changes in [Ca2+]o. The PTH was enhanced by treatments that increase Ca2+ entry into cells including perfusion with elevated [Ca2+]o, with picrotoxin or with tetraethylammonium ion (TEA). The K+ conductance blocker 4-AP had no consistent effect on the PTH. The PTH was potently blocked by the membrane-permeant forms of cAMP, dibutyryl- and 8-bromo-cAMP. However, phorbol esters that activate protein kinase C and carbachol, which usually block the same potential that is blocked by cAMP, did not depress the PTH. The cardiac glycosides dihydro-ouabain and strophanthidin had only small and variable effects on the PTH.(ABSTRACT TRUNCATED AT 250 WORDS)

Action Potentials↗
PubMed1990

Sexual dysfunction in Parkinson's disease.

Sexual functioning was investigated in 50 parkinsonian male and female patients using a questionnaire. A loss of sexual interest and functioning was reported in a high percentage of patients. Depression was not prevalent but 70% had some evidence of autonomic nervous system dysfunction that may be related to sexual dysfunction. It is concluded that the sexual function is frequently impaired in Parkinson's disease.

Aged↗