Biomedical subjects

C Prior

Publications and source records attributed to C Prior.

At least 55 records · Page 3Linked to original sources

PubMed1995

Prejunctional actions of muscle relaxants: synaptic vesicles and transmitter mobilization as sites of action.

1. Nicotinic antagonists such as tubocurarine affect acetylcholine release from motor nerve terminals at the neuromuscular junction. 2. Electrophysiological studies comparing the prejunctional actions of tubocurarine to those of vesamicol and vecuronium have been used to provide an insight into the mechanisms involved in the prejunctional effects of tubocurarine-like compounds. 3. The observed prejunctional actions of tubocurarine can be accounted for by a model in which the compound has two separately identifiable effects on the nerve terminal. At low frequencies of nerve stimulation tubocurarine augments acetylcholine release while at high frequencies of nerve stimulation tubocurarine depresses acetylcholine release. 4. Both of the effects of tubocurarine on acetylcholine release are a consequence of a change in the number of quanta within the nerve terminal immediately available for release upon nerve stimulation. 5. On the basis of our experimental observations, we suggest that the two prejunctional effects of tubocurarine are mediated through two pharmacologically distinct prejunctional nAChRs.

Animals↗

PubMed1995

The heterogeneity of vesicular acetylcholine storage in cholinergic nerve terminals.

The vesicular hypothesis of quantal acetylcholine release describes the process by which discrete packages (or quanta) of the transmitter are released from nerve terminals through the exocytosis of the content of synaptic vesicles. However, cholinergic synaptic vesicles can no longer be vaguely regarded as simple membrane bound 'sacks' of the transmitter. Modern molecular, biochemical, morphological and electrophysiological research has revealed them to be complex cellular structures with a heterogeneous mixture of functions. Thus, not all synaptic vesicle populations are formed under the same circumstances and there are variations in the releasability of synaptic vesicle populations. This review briefly outlines some of the experimental research that has lead to our current thinking on the heterogeneity of vesicular acetylcholine storage in cholinergic nerve terminals. In addition, a model for vesicular acetylcholine storage and release is presented that attempts to accommodate many of the modern ideas concerning cholinergic synaptic vesicle function and interaction.

Acetylcholine↗

PubMed1995

Neuromuscular blocking profile of the vecuronium analogue, Org-9487, in the rat isolated hemidiaphragm preparation.

1. The neuromuscular effects of the short-acting aminosteroid muscle relaxant Org-9487 have been studied in the in vitro rat phrenic nerve/hemidiaphragm preparation by use of twitch tension and electrophysiological recording techniques. 2. Org-9487 (5-100 microM) produced a concentration-dependent decrease in the amplitude of twitches (0.1 Hz) and tetanic contractions (50 Hz) evoked by motor nerve stimulation. The compound produced fade of force during both 50 Hz stimulation and train-of-four stimulation at 2 Hz, indicating a prejunctional component of action. 3. Anticholinesterases only partially reversed the effect of Org-9487 on twitch responses. This was possibly because, at the concentrations required to block twitches in the rat, Org-9487 itself was found to possess significant anticholinesterase activity. 4. Org-9487 (3 microM) increased the rundown of endplate current amplitudes during a 2 s train of 50 Hz nerve stimulation. This was because Org-9487 increased the quantal content of the first endplate current in the train without affecting acetylcholine release towards the latter part of the train. 5. Org-9487 (10 microM) produced a voltage-dependent decrease in the time constant of decay of endplate currents at 32 degrees C and 0.5 Hz, indicative of a block of endplate ion channels. The blocking rate constant increased with membrane hyperpolarization.

Acetylcholine↗

PubMed1994

Factors governing the appearance of small-mode miniature endplate currents at the snake neuromuscular junction.

At the snake neuromuscular junction, following a short period of high frequency motor nerve stimulation, a population of 'small-mode' miniature endplate currents (MEPCs) is seen. These small-mode MEPCs are believed to be due to the release of acetylcholine from incompletely refilled recycling synaptic vesicles [Searl et al., Neuroscience, 35 (1991) 145-156]. This study determines the role of the trans-vesicular membrane proton gradient in the generation of small-mode MEPCs. Preserving the trans-vesicular membrane proton gradient during synaptic vesicle exocytosis by exposure of snake nerve/muscle preparations to an extracellular pH approximately equal to the intravesicular pH, leads to an augmentation of the amplitude of the stimulation-induced small-mode MEPCs. Conversely, pretreatment of snake neuromuscular preparations with 10 mM ammonium ions, to buffer intravesicular protons and hence dissipate the trans-vesicular membrane proton gradient, leads to an inhibition of the stimulation-induced appearance of small-mode MEPCs. The data are consistent with the theory that the reduced acetylcholine content of recycled synaptic vesicles in the snake is a consequence of an incomplete restoration of the trans-vesicular membrane proton gradient following synaptic vesicle exocytosis. Thus, in recycling synaptic vesicles the limiting step in the refilling process appears to be generation of the trans-membrane proton gradient and not the transport of acetylcholine into the vesicle.

Ammonium Chloride↗

PubMed1994

Serum levels of interleukin 6, interleukin 8, and C-reactive protein after human allogeneic bone marrow transplantation.

Serum levels of interleukin 6 (IL-6) and C-reactive protein (CRP) were measured every second day from day -6 to day +86 in 24 patients undergoing allogeneic (n = 23) and syngeneic (n = 1) bone marrow transplantation (BMT). Endogenous serum levels of IL-6, IL-8, and CRP were further analyzed during complications after BMT, such as fever of unknown origin (FUO), severe infectious complications and acute graft-versus-host disease (GVHD). In addition, CRP levels were measured in 10 patients with interstitial pneumonitis of various origins (CMV, idiopathic). In all 24 patients IL-6 and CRP levels showed a characteristic monophasic pattern. After a slight decrease in the first days after BMT, a significant increase was observed, starting on day +3/+5 (P < 0.05) and reaching peak levels on day +9/+11 (P < 0.01). CRP had a similar pattern, with an increase in serum levels on day +3/+5 and maximum levels one to three days after the IL-6 peak was reached. The magnitude of the peak was related to the development of complications in the further course of BMT and was high in patients with and low in patients without complications. Serum levels of both molecules returned to baseline after day 14 posttransplant. Increased IL-6 and CRP levels were observed in the further course of BMT during severe infections or FUO either on the day of clinical onset (IL-6) or three days later (CRP), but not during acute GVHD grade III/IV. CMV interstitial pneumonitis (CMV-IP) was accompanied by an increase in CRP levels, while no such elevations were observed in patients with idiopathic interstitial pneumonitis (IIP). Elevated IL-8 serum levels occurred during bacterial infections, but to a lesser amount also during GVHD and CMV-IP. In conclusion, a characteristic pattern of IL-6 and CRP was observed after allogeneic BMT and a further increase associated with infectious complications. Since no significant elevations were seen in patients with GVHD, we conclude that both molecules are not involved in the induction of GVHD and might be useful diagnostic tools for the prediction and diagnosis of infectious complications after BMT. In contrast, assessment of IL-8 serum values does not permit clinical complications to be specified.

Adolescent↗

PubMed1994

Nicotinic antagonist-produced frequency-dependent changes in acetylcholine release from rat motor nerve terminals.

1. The frequency (0.5-150 Hz) and calcium dependence (0.5-2.0 mM) of the effects of the nicotinic antagonist tubocurarine (0.2 microM) on acetylcholine (ACh) liberation from motor nerve terminals has been examined using binomial analysis of quantal transmitter release. 2. At an extracellular calcium ion concentration ([Ca2+]o) of 2.0 mM, tubocurarine produced a decrease in the endplate current (EPC) quantal content of approximately 30% at high frequencies of motor nerve stimulation (50-150 Hz). In contrast, at low frequencies of stimulation (0.5-1.0 Hz), tubocurarine enhanced the EPC quantal content by approximately 20%. 3. The enhancement of EPC quantal content produced by tubocurarine at low frequencies of motor nerve stimulation was [Ca2+]o dependent, being abolished when [Ca2+]o was lowered from 2.0 to 0.5 mM. In contrast, the decrease in quantal content produced by tubocurarine at high frequencies of motor nerve stimulation was independent of [Ca2+]o, being approximately 30% at all calcium ion concentrations studied. 4. In direct contrast to tubocurarine, the nicotinic antagonist vecuronium (1.0 microM) produced no increase in EPC quantal content at low frequencies of nerve stimulation. However, at high frequencies of nerve stimulation it decreased EPC quantal content to a similar extent to 0.2 microM tubocurarine. The frequency-dependent decrease in EPC quantal content produced by 1.0 microM vecuronium in 2.0 mM [Ca2+]o was very similar to that seen with 0.2 microM tubocurarine in 0.5 mM [Ca2+]o. 5. Binomial analysis revealed that all the changes in EPC quantal content associated with both nicotinic antagonists were due to changes in the size of the pool of quanta in the nerve terminal available for immediate release with no effect on the probability of release of an individual quantum. 6. The results are interpreted in terms of two separately identifiable prejunctional actions of the nicotinic antagonists, both involving an action at nicotinic ACh receptors situated on the motor nerve terminal. Thus, at high frequencies of motor nerve stimulation tubocurarine and vecuronium produce a [Ca2+]o-independent decrease in ACh release, probably through an inhibitory action on a positive-feedback prejunctional nicotinic autoreceptor closely related to the muscle-type nicotinic ACh autoreceptor. However, at low frequencies of motor nerve stimulation we suggest that tubocurarine, but not vecuronium, produces a [Ca2+]o-dependent increase in ACh release through an action at a negative-feedback prejunctional neuronal-type nicotinic ACh autoreceptor.

Acetylcholine↗

PubMed1994

In-vitro smooth muscle relaxant activity of a series of vecuronium analogues in the rat aorta.

The ability of a series of 17-ester analogues of vecuronium to elicit a direct relaxant effect on vascular smooth muscle has been studied using rat isolated aortic rings contracted with 40 mM KCl. The IC50 for inhibition of KCl-induced contractions increased with increasing size of the 17-ester substituent, such that vecuronium (17 beta-acetate) was the least potent with an IC50 of around 50 microM and Org-9827 (17 alpha-pivalate) was the most potent with an IC50 of around 5 microM. In addition, for the weaker-acting compounds, the 17 alpha-esters were more potent than their corresponding 17 beta-esters, although this difference was lost as the size of the 17-ester substituent increased. From the results obtained here, it is concluded that the hypotensive activity of some of the newer neuromuscular blocking steroids seen in cats, pigs and dogs in-vivo is probably, at least in part, a consequence of a direct relaxant effect of the compound on vascular smooth muscle through inhibition of voltage-activated, L-type, calcium channels. This may have both advantageous and disadvantageous clinical consequences when using large doses of one of the newer vecuronium analogues with a low relative neuromuscular-blocking potency.

Animals↗

PubMed1994

[Spectroscopic analysis of biliary calculi: correlations of the type of calculi and clinical data of 25 consecutive surgical patients].

The Authors considering cholelithiasis as an heterogenic pathological entity report their experience of 25 surgical consecutive patients: 20 with cholesterol or combination gallstones and 5 with black pigmented gallstones. In this series the most frequent factors associated with cholesterol gallstones were LDL hypercholesterolemia and hypertriglyceridemia; while the most frequent factors associated with black pigmented gallstones were hepatopathies. The most frequent symptom was dyspepsia. Only the black pigmented and the mixed gallstones were associated with jaundice and pancreatitis. According to the Literature infection is associated to brown pigment gallstones in 95% of cases, in this series infection is rarely associated with other types of gallstones. Treatment with oral bile salts is useful only in pure cholesterol gallstones, so the distinction among different types of gallstones is useful not only for a better knowledge of their pathogenesis but also for a correct choice of the therapeutic options.

Aged↗

PubMed1993

Low-affinity glucose carrier gene LGT1 of Saccharomyces cerevisiae, a homologue of the Kluyveromyces lactis RAG1 gene.

A low-affinity glucose transporter gene of Saccharomyces cerevisiae was cloned by complementation of the rag1 mutation in a strain of Kluyveromyces lactis defective in low-affinity glucose transport. Gene sequence and effects of null mutation in S. cerevisiae were described. Data indicated that there are multiple genes for low-affinity glucose transport.

Amino Acid Sequence↗

PubMed1993

Electrophysiological analysis of transmission at the skeletal neuromuscular junction.

The review is divided into two sections. The first deals with methods and problems associated with performing electrophysiological experimentation on the skeletal muscle neuromuscular junction. The second section concentrates on the computer analysis of electrophysiological data. In the first section, the various techniques available for producing skeletal muscle paralysis are described. These include the use of pharmacological manipulations, such as an excess of magnesium ions or a competitive postjunctional nicotinic acetylcholine antagonist, physiological manipulations, such as cutting the muscle fibers, and the muscle fiber sodium channel toxin, mu-conotoxin. Also, in this section, a comparison is made of the use of voltage- and current-recording techniques, including descriptions of, and solutions to, the problems associated with membrane capacitance, nonlinear summation, membrane space constant, and electrical and mechanical interference. In the second section, details are given of the types of computer system commonly used for the analysis of electrophysiological data and also the requirements of the data analysis software. The use of computer algorithms for signal detection, signal evaluation, signal averaging, and curve fitting are qualitatively described, along with some of the problems and pitfalls often associated with these methods.

Animals↗

PubMed1993

Acetylcholine transport, storage, and release.

ACh is released from cholinergic nerve terminals under both resting and stimulated conditions. Stimulated release is mediated by exocytosis of synaptic vesicle contents. The structure and function of cholinergic vesicles are becoming known. The concentration of ACh in vesicles is about 100-fold greater than the concentration in the cytoplasm. The AChT exhibits the lowest binding specificity among known ACh-binding proteins. It is driven by efflux of protons pumped into the vesicle by the V-type ATPase. A potent pharmacology of the AChT based on the allosteric VR has been developed. It has promise for clinical applications that include in vivo evaluation of the density of cholinergic innervation in organs based on PET and SPECT. The microscopic kinetics model that has been developed and the very low transport specificity of the vesicular AChT-VR suggest that the transporter has a channel-like or multidrug resistance protein-like structure. The AChT-VR has been shown to be tightly associated with proteoglycan, which is an unexpected macromolecular relationship. Vesamicol and its analogs block evoked release of ACh from cholinergic nerve terminals after a lag period that depends on the rate of release. Recycling quanta of ACh that are sensitive to vesamicol have been identified electrophysiologically, and they constitute a functional correlate of the biochemically identified VP2 synaptic vesicles. The concept of transmitter mobilization, including the observation that the most recently synthesized ACh is the first to be released, has been greatly clarified because of the availability of vesamicol. Differences among different cholinergic nerve terminal types in the sensitivity to vesamicol, the relative amounts of readily and less releasable ACh, and other aspects of the intracellular metabolism of ACh probably are more apparent than real. They easily could arise from differences in the relative rates of competing or sequential steps in the complicated intraterminal metabolism of ACh rather than from fundamental differences among the terminals. Nonquantal release of ACh from motor nerve terminals arises at least in part from the movement of cytoplasmic ACh through the AChT located in the cytoplasmic membrane, and it is blocked by vesamicol. Possibly, the proteoglycan component of the AChT-VR produces long-term residence of the macromolecular complex in the cytoplasmic membrane through interaction with the synaptic matrix. The preponderance of evidence suggests that a significant fraction of what previously, heretofore, had been considered to be nonquantal release from the motor neuron actually is quantal release from the neuron at sites not detected electrophysiologically.(ABSTRACT TRUNCATED AT 400 WORDS)

Acetylcholine↗

PubMed1993

Successful treatment of spinal sarcoidosis by high-dose intravenous methylprednisolone.

A man with known pulmonary sarcoidosis presented with paraplegia and a rod-shaped increase in T2 signal intensity in his cervical and upper thoracic spine. Initial treatment efforts using oral doses of 40 mg of methyl-prednisolone were futile, but intravenous bolus therapy (500 mg of methyl-prednisolone daily for 1 week) led to long-lasting improvement of his neurological status and to normalization of MRI findings.

Adult↗

PubMed1993

Characteristics of early onset esotropia.

Some 115 patients with a reported onset of esotropia within the first six months of life were studied retrospectively to assess ocular findings and the evolution of any changes with time. All patients had been treated by one ophthalmologist and one orthoptist since 1972. Of the 115 patients, 27% had an accommodative element associated with the esotropia. Patients with an accommodative esotropia had higher levels of hypermetropia when compared to the non-accommodative group, but there were no other distinguishing characteristics. The groups exhibited a large variation in angle size, ranging from four to 45 degrees at the initial visit. The presence of fusion, amblyopia and the degree of hypermetropia had no significant effect on the course of the squint. Amblyopia was noted in 67% of cases and appeared to stabilise at a later-than-expected age, with 66% of patients with amblyopia stabilising between eight and 11 years. Surgical intervention had no effect on the incidence of amblyopia at the initial or final visits.

Accommodation, Ocular↗

PubMed1993

The long-term results of surgical correction of childhood esotropia.

The results of surgical management by one ophthalmologist of 102 patients with congenital esotropia and 74 patients with acquired esotropia in childhood were analysed. The majority of patients had undergone a monocular recession-resection procedure, with 91% and 93% of patients showing a reduction in the angle, of more than five degrees, following surgery for congenital and acquired esotropia respectively. Unexpectedly, varying the amount of lateral rectus resection from 3 to 6 mm, when combined with a constant 5 mm medial rectus recession, did not produce significantly different amounts of change in the ocular alignment after surgery. Patients with congenital esotropia generally developed a stable postoperative angle later than patients with acquired esotropia. The degree of improvement of ocular alignment with surgery was independent of hypermetropia, presence of preoperative amblyopia or fusion.

Amblyopia↗

PubMed1993

The hexokinase gene is required for transcriptional regulation of the glucose transporter gene RAG1 in Kluyveromyces lactis.

The RAG1 gene of Kluyveromyces lactis encodes a low-affinity glucose/fructose transporter. Its transcription is induced by glucose, fructose, and several other sugars. The RAG4, RAG5, and RAG8 genes are trans-acting genes controlling the expression of the RAG1 gene. We report here the characterization of one of these genes, RAG5. The nucleotide sequence of the cloned RAG5 gene indicated that it encodes a protein that is homologous to hexokinases of Saccharomyces cerevisiae. rag5 mutants showed no detectable hexokinase or glucokinase activity, suggesting that the sugar kinase activity encoded by this gene is the only hexokinase in K. lactis. Both high- and low-affinity transport systems of glucose were affected in rag5 mutants. The defect of the low-affinity component was found to be due to a block of transcription of the RAG1 gene by the hexokinase mutation. In vivo complementation of the rag5 mutation by the HXK2 gene of S. cerevisiae and complementation of hxk1 hxk2 mutations of S. cerevisiae by the RAG5 gene showed that RAG5 and HXK2 were equivalent for sugar-phosphorylating activity but that RAG5 could not restore glucose repression in the S. cerevisiae hexokinase mutants.

Amino Acid Sequence↗

PubMed1992

Multimodal therapy of small cell lung cancer in TNM stages I through IIIa.

Since 1977, Innsbruck University Hospital has been employing a multimodal therapy concept for small cell bronchial carcinomas in stages I to IIIa. This concept includes all three treatment forms effective in this tumor, namely, chemotherapy, surgery, and radiotherapy. The therapy scheme is stage-dependent and begins in stages T1-3 N0-1 with lung resection and in stage N2 with chemotherapy. To date, 45 patients have been included in a prospective, nonrandomized (phase II) trial: 7 in TNM stage I, 11 in stage II, and 27 in stage IIIa (6 T3 and 21 N2). The actuarial 5-year survival rate of the entire group (including therapy-related lethality, early recurrences, and protocol violations) is 36%; it is 57% for those in stage I, 28% for those in stage II, and 34% for those in stage IIIa. Median survival time is 18 months. Patients with completed multimodal treatment have a 5-year survival rate of 56% regardless of disease stage. Three patients died of tumor-unrelated causes after 47, 52, and 54 months.

Adult↗

PubMed1992

alpha-Conotoxin GI produces tetanic fade at the rat neuromuscular junction.

The ability of the marine snail toxin, alpha-conotoxin GI, to produce blockade of singly evoked twitches and to produce tetanic and train-of-four fade has been determined in the isolated rat hemidiaphragm preparation. Results were compared to those obtained with a reversible (vecuronium) and an irreversible (alpha-bungarotoxin) nicotinic acetylcholine antagonist and have been interpreted in terms of relative effects on post- and prejunctional nicotinic acetylcholine receptors at the neuromuscular junction. alpha-Conotoxin GI (0.5-2 microM) produced a concentration-dependent, readily reversible, decrease in the peak amplitude of single twitches and 50 Hz tetani, and an increase in tetanic and train-of-four fade. alpha-Conotoxin GI was consistently 2-3-fold more potent than vecuronium with respect to all of the measured tension parameters. Both alpha-conotoxin GI and vecuronium were approximately 2-fold more potent in producing tetanic fade and in blocking tetanic contractions than in blocking single twitches. In contrast to both alpha-conotoxin GI and vecuronium, alpha-bungarotoxin (0.13 microM) reduced the peak amplitude of both single twitches and 50 Hz tetani to the same extent without the appearance of a large degree of tetanic or train-of-four fade. Based on a comparison of the in vitro time course of neuromuscular block and of the relative effects of vecuronium, alpha-conotoxin GI and alpha-bungarotoxin on twitches, tetani and trains-of-four, we conclude that alpha-conotoxin GI has both pre- and postjunctional activity at the neuromuscular junction. In this respect, alpha-conotoxin GI resembles the clinically used competitive neuromuscular blocking drugs rather than the irreversible snake alpha-neurotoxins.

Animals↗

PubMed1992

The pharmacology of vesamicol: an inhibitor of the vesicular acetylcholine transporter.

1. Vesamicol (2-[4-phenylpiperidino] cyclohexanol) inhibits the transport of acetylcholine into synaptic vesicles in cholinergic nerve terminals. 2. Recent pharmacological studies of the effects of vesamicol on skeletal neuromuscular transmission have revealed a pattern of activity for the compound consistent with the neurochemical observation of the mechanism of action of the compound. 3. Pharmacological manipulation of vesicular acetylcholine transport has been used to investigate the recycling and mobilization of synaptic vesicles within cholinergic nerve terminals. 4. In addition to its effects on vesicular acetylcholine transport, vesamicol also possesses some sodium channel and alpha-adrenoceptor blocking activity. 5. Vesamicol clearly represents a unique tool for investigating presynaptic mechanisms in cholinergic nerve terminals.

Acetylcholine↗