Biomedical subjects
T H Brown
Publications and source records attributed to T H Brown.
Long-term synaptic potentiation in the amygdala.
The manner in which the circuitry of the amygdala computes its suspected mnemonic functions has been a mystery, partly because the cytoarchitectual complexity of this nuclear group has impeded the necessary cellular analysis. Here we report in vitro methods and results that may help elucidate cellular learning mechanisms in amygdala neurons. The amygdala brain slice preparation was combined with the single-electrode clamp (SEC) technique for intracellular analysis of membrane properties and synaptic responses. With respect to the active and passive membrane properties, we found considerable diversity among the population of cells that were sampled in the lateral and basolateral nuclei (n = 85). Synaptic inputs to these neurons were studied by stimulating the external capsule (EC), which was shown to produce a complex response that typically consisted of an excitatory followed by an inhibitory component. Based on several criteria, the excitatory component appeared to reflect a monosynaptic connection from the EC. One immediate goal was to discover whether the excitatory component displays the phenomenon of long-term potentiation (LTP)--a persistent increase in synaptic strength that can be induced by brief periods of the appropriate synaptic stimulation. Indeed, we found that high-frequency (100 Hz) stimulation of the EC induced LTP in 80% of the cells from which suitable recordings were obtained (n = 20). This finding of LTP in the amygdala is significant in regard to current efforts to explore linkages between this use-dependent form of synaptic plasticity and rapid kinds of associative learning.
A modified technique for the estimation of the number of infective nematode larvae present on pasture, and its application in the field under South Australian conditions.
A modified technique for the recovery of larvae from pasture is described involving two centrifugations of pasture washings in a solution of potassium iodide. On average, the technique recovered 96% of larvae and was simple to perform. At three sites in South Australia (rainfall 550-330 mm year-1), the numbers of larvae present on pasture each month using this technique was compared with results obtained using one or four tracer sheep. The general pattern of larval availability was similar using the two methods, but discrepancies were noted. In some instances, particularly when numbers of larvae were low, pasture sampling underestimated the numbers of larvae available to sheep; in other situations, when the numbers of larvae were high, tracer sheep probably underestimated the number being ingested. Increasing the numbers of tracer sheep from one to four did not appreciably increase the correspondence between the two methods.
Reversible inhibitors of the gastric (H+/K+)-ATPase. 1. 1-Aryl-4-methylpyrrolo[3,2-c]quinolines as conformationally restrained analogues of 4-(arylamino)quinolines.
The 4-(arylamino)quinoline 4, previously described as an antiulcer compound, is shown to be an inhibitor of the gastric (H+/K+)-ATPase. It is postulated that 1-arylpyrrolo[3,2-c]quinolines 6 act as conformationally restrained analogues of 4. A series of derivatives of 6 has been prepared and shown to be potent inhibitors of the target enzyme in vitro. Substitution in the ortho position of the aryl ring is important for activity. Unsaturation in the 5-membered ring makes little difference, but introduction of heteroatoms into the same ring markedly reduces activity. In more detailed kinetic experiments, 15c and 4 both show reversible, K(+)-competitive binding to the enzyme, with submicromolar Ki values. The compounds appear to act at the lumenal face of the enzyme and to require protonation for activity. Several compounds in the series are shown to be potent inhibitors of pentagastrin-stimulated acid secretion in the rat.
Biophysical model of a Hebbian synapse.
We present a biophysical model of electrical and Ca(2+) dynamics following activation of N-methyl-D-aspartate (NMDA) receptors located on a dendritic spine. The model accounts for much of the phenomenology of the induction of long-term potentiation at a Hebbian synapse in hippocampal region CA1. Computer simulations suggested four important functions of spines in this Ca(2+)-dependent synaptic modification: (i) compartmentalizing transient changes in [Ca(2+)] to just those synapses that satisfy the conjunctive requirement for synaptic modification; (ii) isolating the spine head from changes in the [Ca(2+)] at the dendritic shaft; (iii) amplifying the concentration changes at those synapses; and (iv) increasing the voltage dependence of the processes underlying long term potentiation induction. This proposed role of spines in the regulation of Ca(2+) dynamics contrasts with traditional approaches to spine function that have stressed electronic properties. This model can be used to explore the computational implications of Hebbian synapses.
Prevalence of resistance in sheep nematode populations to benzimidazole and levamisole anthelmintics in the high rainfall areas of South Australia.
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Hebbian synapses: biophysical mechanisms and algorithms.
We have examined the evolution of the concept of a Hebbian synaptic modification and have suggested a contemporary definition. The biophysical mechanism demonstrated in vitro to control the induction of one type of hippocampal LTP has been shown to satisfy our definition of a Hebbian synaptic modification. Whether this biophysical mechanism is involved in the organization of behavior in the manner that Hebb originally envisioned remains to be seen. We have also summarized several modification algorithms that have been explored in theoretical studies of learning in adaptive networks. These algorithms also satisfied our definition of a Hebbian modification, but their relationships to known neurobiology require further exploration. By reviewing the biophysical mechanisms and formal algorithms together, we have exposed obvious similarities and differences. Such comparisons may help bridge the gap between computational theory and knowledge of the neurobiology of use-dependent synaptic change. Current models of LTP reveal that the activity-modification relationships are extremely sensitive to the biophysical/molecular details. The activity-modification relationships obviously can have a major influence on adaptive neurodynamics at the network level. As more accurate representations of the biological complexity and diversity are introduced into adaptive network simulations, we expect to gain new insights into the classes of computation that particular networks are capable of performing.
The alkaline shift in gastric pH after cholecystectomy.
Previous studies using cholescintigraphy and measurement of bile salts in gastric juice have demonstrated that duodenogastric reflux is increased after cholecystectomy, a factor that may contribute to postoperative complaints in some patients. We studied 24-hour continuous gastric pH in healthy subjects, patients with cholelithiasis, and patients who had undergone cholecystectomy. Cholecystectomy decreased the percentage of time that gastric pH is below 2 and increased the time it is above 4 and 6. Furthermore, there was a greater increase in the more alkaline pH values in patients who were symptomatic than in those who were asymptomatic. The results demonstrated that cholecystectomy is associated with an alkaline shift in the 24-hour gastric pH profile that is most marked in symptomatic patients. This suggests that gastric alkaline episodes may be related to some postcholecystectomy symptoms.
Delayed gastric ulcer healing after extirpation of submandibular glands is sex-dependent.
This study examines the effect of excision of the submandibular salivary glands, the main source of epidermal growth factor (EGF), and the role of gender on the healing of acetic acid-induced gastric ulcers in rats. In male rats excision of the submandibular glands delayed ulcer healing. At 15 and 25 days the unhealed ulcer areas were significantly larger in the sialoadenectomy group than in control animals, and fewer completely healed ulcers were seen in this group at 25 days. Ulcer healing in female rats was slower. At day 25 ulcers were healed in 12% of female rats with intact salivary glands, compared with 68% in males. Female rats also showed larger unhealed ulcer areas after sialoadenectomy than controls. We conclude that removal of the main source of EGF in the gastrointestinal tract is associated with a delay in healing of gastric ulcers. The significant difference in healing observed between female and male rats may be influenced by the known androgenic regulation of EGF production in the salivary glands.
Long-term synaptic potentiation.
Long-term synaptic potentiation (LTP) is a leading candidate for a synaptic mechanism of rapid learning in mammals. LTP is a persistent increase in synaptic efficacy that can be quickly induced. The biophysical process that controls one type of LTP is formally similar to a synaptic memory mechanism postulated decades ago by the psychologist Donald Hebb. A key aspect of the modification process involves the N-methyl-D-aspartate (NMDA) receptor-ionophore complex. This ionophore allows calcium influx only if the endogenous ligand glutamate binds to the NMDA receptor and if the voltage across the associated channel is also sufficiently depolarized to relieve a magnesium block. According to one popular hypothesis, the resulting increase in the intracellular calcium concentration activates protein kinases that enhance the postsynaptic conductance. Further biophysical and molecular understanding of the modification process should facilitate detailed explorations of the mnemonic functions of LTP.
The African connection. Cotton Mather and the Boston smallpox epidemic of 1721-1722.
The contributions of black Americans to early American culture have still not been fully explored or given the attention deserved. A case in point is the significant contributions African slaves made to 18th-century American folk medicine. A review of the events incident to the smallpox epidemic in Boston in 1721 will illustrate the degree to which some reputable men of science depended on the testimony and experience of Africans in dealing with a particularly dread disease.
Sequential development of resistance to thiabendazole and levamisole in nematodes of sheep.
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Changes in resistance of Ostertagia spp. to thiabendazole following natural selection or treatment with levamisole.
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Videomicroscopy of acute brain slices from amygdala and hippocampus.
Video-enhanced contrast, differential-interference contrast microscopy (VEC-DICM) was used to visualize the cytoarchitecture and subcellular neuronal structure of acute brain slices from rat hippocampus and amygdala. Even at low-power magnification, the VEC-DICM system vastly improved our ability to visualize and examine the gross organization of the tissue. With medium-power magnification, the neuronal somata and proximal dendrites were clearly visible. With high-power magnification, some of the subcellular details could be clearly discerned--including cell nuclei, cell nucleoli, fine dendritic processes, and varicosities that may be synaptic expansions. We conclude that improved optical techniques should be valuable to cellular neurobiologists interested in structure-function relationships in brain slices.
Development of a new physicochemical model for brain penetration and its application to the design of centrally acting H2 receptor histamine antagonists.
A rational approach to the design of centrally acting agents is presented, based initially upon a comparison of the physicochemical properties of three typical histamine H2 receptor antagonists which do not readily cross the blood-brain barrier with those of the three brain-penetrating drugs clonidine (6), mepyramine (7) and imipramine (8). A good correlation was found between the logarithms of the equilibrium brain/blood concentration ratios in the rat and the partition parameter, delta log P, defined as log P (1-octanol/water)-log P (cyclohexane/water), which suggests that brain penetration might be improved by reducing overall hydrogen-bonding ability. This model has been employed as a guide in the design of novel brain-penetrating H2 antagonists by the systematic structural modification of representatives of different structural types of H2 antagonists. Although marked increases in brain penetration amongst congeners of cimetidine (1), ranitidine (9), and tiotidine (10) were achieved, no compound was found with an acceptable combination of H2 antagonist activity (-log KB in the guinea pig atrium greater than 7.0) and brain penetration (steady-state brain/blood concentration ratio greater than 1.0). Conversely, structural modification of N-[[(piperidinyl-methyl)phenoxy]propy]acetamide (30) led to several potent, novel compounds which readily cross the blood-brain barrier. One of these, zolantidine (SK&F 95282, 41), whose -log KB is 7.46 and steady-state brain/blood ratio is 1.4, has been identified for use in studying histaminergic H2 receptor mechanisms in brain. Comparison of delta log P values with the logarithms of the brain/blood ratios for 20 structurally diverse compounds for which data became available confirms a highly significant correlation and supports the general validity of this model.
A harness for 24-hour pH-monitoring in the dog.
Twenty-four hour pH monitoring is used widely in the field of upper gastrointestinal disease. This technique allows the study of pH profiles in normal subjects and those with esophageal, gastric, or duodenal disease. However, it has not been possible to study ambulatory pH in animals. We have designed and developed a harness to carry a pH recorder that enables 24-hour pH studies to be performed in the dog. We studied pH profiles in 10 dogs. The harness is adaptable and could be used for other long-term physiological measurements.
Toxicity of H2-receptor antagonists to isolated rat hepatocytes: structure-activity relationships.
Oxmetidine is a potent and specific antagonist of the histamine H2-receptor. Oxmetidine is also cytotoxic to isolated rat hepatocytes through inhibition of mitochondrial oxidative phosphorylation. The purpose of this investigation was to test a variety of H2-receptor antagonists that are structural analogs of oxmetidine in an attempt to identify a critical structural component or a physicochemical property of the molecule which may be responsible for cytotoxicity. Six histamine receptor H2-antagonists were tested. The minimum drug concentrations that caused 100% cell death (leakage of intracellular lactate dehydrogenase and loss of intracellular potassium) ranged from 0.87 to 22.50 mM for the analogs tested. At toxic concentrations, two of the least potent analogs, SK&F 92909 and SK&F 9205A both caused a rapid decrease in hepatocyte O2 consumption and ATP content which occurred before any evidence of cell injury. The potency of these molecules as cytotoxicants to isolated hepatocytes did not correlate with their potency as histamine H2-receptor antagonists whereas there was a significant correlation between increasing potency and increasing octanol/water partition coefficients. These data suggest that lipid solubility may be a key factor in the cytotoxicity of this class of drugs to isolated rat hepatocytes.
The effect of an intragastric balloon on weight loss, gastric acid secretion, and serum peptide levels.
The results of our preliminary experience with the gastric balloon program for weight loss in morbidly obese patients are reported. In a pilot project, we measured gastric-acid secretion, gastrin and cholecystokinin (CCK) levels in ten patients before and during balloon therapy in a study of the impact of the balloon on gastric physiology. Gastric-acid secretion tended to decrease following balloon treatment, while gastrin and CCK levels were unchanged suggesting that weight loss is achieved by mechanisms, which are not mediated by gastrin or CCK. The balloon program was then expanded to a group of 29 patients who met the criteria. They were followed for a period of 4 months. Average weight loss for the group was 31 +/- 4 pounds for a monthly average of 8 pounds. The main complications were gastric ulcers in four patients and a small-bowel obstruction in one patient. Satisfactory weight loss was achieved in 80 per cent of patients, but this benefit must be balanced against a relatively high incidence (17%) of side effects, some of which were quite serious. Therefore, the gastric balloon program should still be considered experimental.