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Biomedical subjects

T H Brown

Publications and source records attributed to T H Brown.

At least 19 recordsLinked to original sources
PubMed1992

Reversible inhibitors of the gastric (H+/K+)-ATPase. 3. 3-substituted-4-(phenylamino)quinolines.

Previously, gastric (H+/K+)-ATPase inhibitors such as 2 have been prepared as analogues of 1a on the presumption that the 3-carbethoxy substituent plays a key role in establishing the orientation of the 4-arylamino group. In this paper we explore further the contribution made to activity by the quinoline 3-substituent. We show that, for compounds bearing such a substituent, only a particular combination of properties provides high activity, both in vitro and as inhibitors of gastric acid secretion in vivo. The ability of the substituent to affect activity by restricting rotation about the Cquin-N bond through a combination of both a pi-electron withdrawal and hydrogen bonding is supported by the current study. However, high activity is only achieved if the effect of this group on the quinoline pK(a) is kept to a minimum. 3-Acyl substituents provide an optimum combination of electronic properties. From this series, compound 17c (SK&F 96067) was shown to be a potent inhibitor of histamine-stimulated gastric acid secretion after oral dosing in the Heidenhain pouch dog and was selected for further development and evaluation in man.

Adenosine Triphosphatases↗
PubMed1992

Reversible inhibitors of the gastric (H+/K+)-ATPase. 2. 1-Arylpyrrolo[3,2-c]quinolines: effect of the 4-substituent.

Further work on compounds 1 has identified the 4-position as a site where substantial modifications are tolerated, leading to analogues which are more potent and less toxic than those described previously. The best compound in the series is 13a (SK&F 96356), which is a potent inhibitor of gastric acid secretion in both the pentagastrin-stimulated rat and the histamine-stimulated dog. This compound shows reversible, K(+)-competitive binding to the enzyme. Because of its fluorescent properties, it is also proving useful in vitro as a probe of the structure and function of the (H+/K+)-ATPase.

Adenosine Triphosphatases↗
PubMed1992

Synchronous aortic and gastrointestinal surgery.

The synchronous performance of aortic and gastrointestinal surgery may hold an increased risk of aortic graft infection. The experience of one surgeon who performed 32 such synchronous operations over a period of 11 years is reviewed. No graft infection occurred and it is concluded that such combined operations may be safer to perform than staged surgery in elderly patients.

Aged↗
PubMed1990

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.

Amygdala↗
PubMed1990

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.

Animals↗
PubMed1990

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.

Adenosine Triphosphatases↗
PubMed1990

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.

Animals↗
PubMed1990

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.

Algorithms↗
PubMed1989

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.

Adolescent↗
PubMed1989

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.

Animals↗
PubMed1988

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.

Animals↗
PubMed1988

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.

Africa↗
PubMed1988

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.

Aging↗