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Biomedical subjects

C Prior

Publications and source records attributed to C Prior.

At least 73 records · Page 4Linked to original sources
PubMed1992

Production and functional characterization of a recombinant fragment of von Willebrand factor (vWF): an antagonist to platelet receptor GP Ib.

We expressed a recombinant peptide fragment (Ser445-Val733) of human von Willebrand factor (vWF), containing the binding domain for the platelet receptor of GP Ib, in E. coli. This 33 kD peptide blocks binding of the intact vWF molecule to GP Ib in the presence of modulators. Thus, it offers potential as an antithrombotic agent. High level expression was achieved in a plasmid construct driven by the bacteriophage T7 promoter. The peptide was solubilized from inclusion bodies in strong chaotrope, then reduced and alkylated. Following purification, formulation at pH 3.5, and lyophilization, the reconstituted experimental product (RG 12986) exists as an equilibrium of monomer and dimer species. When formulated above pH 5.0, soluble aggregates are formed; these solutions have less bioactivity than RG 12986. Interestingly, the non-aggregated state of RG 12986 remains conserved following dilution and incubation with platelet-poor plasma. The overall purification/low pH formulation strategies may be applicable to other E. coli recombinant proteins having a tendency to aggregate following removal of chaotrope near physiologic pH when in a concentrated format.

Cloning, Molecular↗
PubMed1992

Relative pre- and postjunctional effects of a new vecuronium analogue, Org 9426, at the rat neuromuscular junction.

We have studied the relative pre- and postjunctional neuromuscular blocking effects of Org 9426 in the isolated rat hemidiaphragm muscle using twitch tension and electrophysiological recording techniques. Postjunctional effects were assessed from decreases in twitch height and from end-plate current amplitude and time constant of decay. Prejunctional effects were assessed from the fade of tetanic twitch tension and end-plate current amplitude rundown. There were no significant differences between the relative pre- and postjunctional effects of Org 9426 and those of previously studied steroidal neuromuscular blocking compounds. It is concluded, therefore, that the rapid onset and short duration of Org 9426 seen in vivo is not a consequence of a strong prejunctional, relative to postjunctional, blocking effect of the compound.

Androstanols↗
PubMed1992

Induction of lymphocyte proliferation by antigen-pulsed human neutrophils.

We have investigated whether purified antigen-pulsed human neutrophils can induce a proliferative response in purified resting blood lymphocytes. Neutrophils were pulsed with soluble tetanus toxoid (dose range 25-250 Lf/ml) and co-cultured with autologous lymphocytes that had been depleted of MHC class II expressing cells. The antigen-pulsed neutrophils induced an increase of lymphocyte proliferation which was dependent on the antigen dose and the neutrophil/lymphocyte ratios. Neutrophils were less potent than autologous monocytes in stimulating lymphocyte proliferation. Blocking with a monoclonal antibody to a common determinant of the human MHC class II complex failed to reduce the lymphoproliferative effects and allogenic antigen-pulsed neutrophils were also able to elicit lymphocyte proliferation similar to autologous neutrophils. We conclude that antigen-pulsed neutrophils are able to induce lymphocyte proliferation in a non-MHC-restricted fashion.

Antigen-Presenting Cells↗
PubMed1992

In vivo levels and in vitro production of interferon-gamma in fibrosing interstitial lung diseases.

The in vivo role of interferons in the development of fibrosis is not fully understood but it is known that interferons can suppress fibroblast proliferation and collagen synthesis in vitro. We have recently demonstrated that in a group of patients with sarcoidosis having predominant pulmonary involvement, patients with the highest levels of circulating interferon-gamma (IFN-gamma) more frequently resolved on corticosteroids, suggesting that they had a less 'fibrotic' component to their disease. We now report that in two other diseases, where the tendency to develop pulmonary fibrosis is greater than in sarcoidosis, namely cryptogenic fibrosing alveolitis (CFA) and fibrosing alveolitis associated with the systemic connective tissue disease progressive systemic sclerosis (FA + PSS), very few patients have elevations in IFN-gamma in their serum. However, as in sarcoidosis, those with the highest levels responded to corticosteroids (P less than 0.05). Attempts to measure IFN-gamma levels in the lungs, using cell-free bronchoalveolar lavage (BAL) fluid supernatants, were negative in all the study groups, suggesting that these samples may be inadequate for such studies. To investigate whether there might be an intrinsic defect in T lymphocyte function associated with predisposition to fibrosing lung diseases, we then investigated the in vitro production of IFN-gamma by lymphocytes separated from the blood of 18 untreated patients (six with CFA, six with FA + PSS and six with sarcoidosis). IFN-gamma production was impaired in 10 (56%) (two with CFA, four with FA + PSS and four with sarcoidosis). A higher proportion of the fibrosing alveolitis patients (CFA or FA + PSS) with impaired IFN-gamma production have subsequently shown spontaneous lung functional deterioration. These findings suggest that impaired IFN-gamma release might be a potentiating factor in the pathogenesis of these fibrosing lung diseases.

Adult↗
PubMed1992

The effects of vesamicol on trains of endplate currents and on focally recorded nerve terminal currents at mammalian neuromuscular junctions.

1. The effects of vesamicol, an inhibitor of vesicular acetylcholine (ACh) storage, were studied on trains of endplate currents (e.p.cs) in the cut rat hemidiaphragm nerve-muscle preparation and on trains of focally recorded nerve terminal current waveforms in the mouse triangularis sterni nerve-muscle preparation. 2. In the rat, 0.1 and 1 microM (-)-vesamicol produced an enhancement of the rundown of e.p.c. amplitudes during trains of high frequency (50 Hz) nerve stimulation. However, 1 microM (+)-vesamicol had no effect on the rundown of e.p.c. amplitudes. 3. In the mouse, high concentrations of (-)-vesamicol (10-100 microM) produced a concentration- and stimulation-dependent decrease in the amplitude of the second negative-going deflection of focally recorded nerve terminal current waveforms. 4. At 1 mM, (-)-vesamicol produced a stimulation-independent decrease in the amplitude of the first negative-going deflection of the nerve terminal current waveforms, an increase in signal delay and evidence of nerve conduction failure. These all indicate a local anaesthetic-like block of nodal Na(+)-channels. 5. In contrast to its effects on trains of e.p.cs, the effects of vesamicol on the nerve terminal current waveforms were not stereoselective, the (+)-isomer being equipotent with the (-)-isomer. 6. Low concentrations of the Na(+)-channel blocking toxin, tetrodotoxin (15-60 nM), produced similar changes in the focally recorded nerve terminal current waveforms to those seen with vesamicol. 7. It is concluded that the stereoselective rundown of e.p.c. amplitudes produced by (-)-vesamicol is due to an effect, either direct or indirect, on ACh mobilization within motor nerve terminals. Furthermore, in mammalian species, the inhibitory effects of vesamicol on nodal Na+-channels which are seen at high concentrations do not contribute to the principal neuromuscular effects of the compound.

Animals↗
PubMed1992

[Calcofluor-white staining in the identification of Pneumocystis carinii].

Calcofluor white stain is widely used as a fluorescent stain in mycology. Recently, it was found that by calcofluor white staining Pneumocystis carinii cysts exert a highly characteristic staining pattern. We retested fifteen clinical specimens which were known to be positive for Pneumocystis carinii (diagnosis made by a methenamine silver stain). Calcofluor white stain proved to be a simple, rapid, and inexpensive method for detecting Pneumocystis carinii in clinical specimens.

Benzenesulfonates↗
PubMed1991

Alpha-adrenoceptor blocking properties of vesamicol.

The side-effects of vesamicol, an inhibitor of acetylcholine storage, on alpha 1- and alpha 2-adrenoceptors have been studied in the isolated rat vas deferens. Antagonism of alpha 1-adrenoceptors was determined from the ability of vesamicol to reduce contractions elicited by exogenous noradrenaline. Antagonism of alpha 2-adrenoceptors was determined from the ability of vesamicol to block the inhibitory effects of the alpha 2-adrenoceptor agonist clonidine on electrically evoked twitches. In the absence of noradrenaline uptake block, (-)-vesamicol, the isomer active at cholinergic synapses, produced a leftward shift of the noradrenaline concentration-effect curve. This effect was abolished by desipramine suggesting that it is due to an ability of (-)-vesamicol to block uptake1. In the presence of noradrenaline uptake blockers, (-)-vesamicol produced a competitive, non-selective block of both alpha 1- and alpha 2-adrenoceptors with a Kd of around 40 microM (pA2 4.4). (+)-Vesamicol, the isomer that has no activity at cholinergic synapses, was equipotent with the (-)-isomer for blocking alpha 2-adrenoceptors. In addition to its alpha-adrenoceptor antagonist activity, (-)-vesamicol augmented the maximum response of the tissue to exogenous and endogenous noradrenaline. This study was unable to determine the exact nature of this effect. We suggest that the alpha-adrenoceptor blocking activity of vesamicol is a function of the phenylpiperidino moiety of the molecule.

Adrenergic alpha-Antagonists↗
PubMed1991

The effects of a 16-N-homopiperidino analogue of vecuronium on neuromuscular transmission in anaesthetized cats, pigs, dogs and monkeys, and in isolated preparations.

Org 9991, a 16-N-homopiperidinium substituted vecuronium analogue, has been tested for neuromuscular blocking activity in anaesthetized cats, pigs, dogs and monkeys, and in isolated nerve-muscle preparations. Org 9991 exhibited non-depolarizing neuromuscular blocking activity of the competitive type, being reversible by neostigmine and showing no endplate channel blocking action in isolated preparations. In cats, 50% vagal block was observed at doses of Org 9991 approximately 10 times those producing 50% neuromuscular block; no ganglion block was seen at these doses. Effects on blood pressure or heart rate at 90% twitch blocking doses were either minor or absent. The potency and time course of action of Org 9991 remained similar in all four species: i.e. 90% block at ca 200-300 micrograms kg-1; onset time ca 1.2-1.9 min; duration 90% ca 4.5-8.9 min. This study suggests that 16-N-homopiperidinium analogues of vecuronium may provide leads in the quest for a potent non-depolarizing replacement for suxamethonium.

Androstanols↗
PubMed1991

Acetylcholine recycling and release at rat motor nerve terminals studied using (-)-vesamicol and troxpyrrolium.

1. The presynaptic mechanisms governing the release and recycling of synaptic vesicles have been studied by examining the effects of nerve stimulation, (-)-vesamicol (an inhibitor of acetylcholine transport into synaptic vesicles) and troxypyrrolium (an inhibitor of the high-affinity, sodium-dependent, choline uptake system) on endplate currents (EPCs) and miniature endplate currents (MECPs) recorded from motor endplates in cut rat hemidiaphragm preparations. 2. In control experiments, 5 min of 10 Hz nerve stimulation had no effect on either the mean or the distribution of MEPC amplitudes. 3. Nerve stimulation in the presence of (-)-vesamicol (25 nM-10 microM) revealed a population of MEPCs that was unaffected by the compound and a population of MEPCs whose mean amplitude was selectively reduced by the compound. 4. Nerve stimulation in the presence of troxypyrrolium (20 microM) produced a uniform reduction in the amplitude of all MEPCs with no change in the coefficient of variance of MEPC amplitudes. 5. The concentration-dependent effects of (-)-vesamicol on the amplitude of the evoked EPCs paralleled the concentration-dependent effects of the compound on MEPC amplitudes. 6. The results are consistent with the hypothesis that both recycled and performed synaptic vesicles are heterogeneously released from rat motor nerve terminals and that (-)-vesamicol acts selectively on recycling vesicles. In addition, a model of vascular loading that accounts for the different effects of nerve stimulation on MEPC amplitudes in the presence of (-)-vesamicol and troxypyrrolium is described.

Acetylcholine↗
PubMed1991

Increased levels of serum interferon-gamma in pulmonary sarcoidosis and relationship with response to corticosteroid therapy.

The aim of this study was to evaluate serum levels of the lymphokine interferon-gamma (IFNg) in patients with chronic pulmonary sarcoidosis, and to investigate its value as a predictive marker of clinical response to corticosteroid therapy. Twenty-five patients and 28 age-matched control subjects were studied. All the patients had parenchymal shadows (Stage II or Stage III) and none had clinical evidence of extrathoracic disease. Before therapy, serum IFNg levels were significantly higher in the patient group (p less than 0.001), and 20 (80%) had values above the normal range. After oral treatment with corticosteroids for a median 13 months (range, 3 to 49 months) the levels decreased significantly (p less than 0.01). However, the falls were less pronounced in patients who had a better outcome in terms of achieving complete radiographic resolution and in those who improved in forced vital capacity by greater than or equal to 10%. The prognostic value of the pretreatment serum IFNg was explored, and a significant relationship was found between higher pretreatment levels and lower grades or radiographic abnormality assessed 3 yr after commencement of treatment (p less than 0.01). In addition, the patients who had cleared completely while receiving steroids and remained in remission had significantly higher pretreatment serum IFNg levels than did those with incomplete resolution of parenchymal shadows or radiographic relapses (p less than 0.05). We conclude that elevated levels of circulating IFNg are detectable in most untreated patients with Stage II/III pulmonary sarcoidosis and that patients with the highest levels appear to have a better chance of achieving complete resolution with corticosteroid therapy.

Adult↗
PubMed1990

Cytomegalovirus pneumonitis in heart-lung transplant recipients: histopathology and clinicopathologic considerations.

Three cases of cytomegalovirus (CMV) pneumonitis in heart-lung transplant recipients are presented, and the clinical course and autopsy findings described. The patients survived transplantation for 15, 6, and 2 months, respectively. Cytomegalovirus pneumonitis was diagnosed between 5 and 12 weeks postoperatively, and was still detectable in two of the patients at postmortem examination. In one patient, at autopsy there was no further evidence of CMV pneumonitis 3 months after its onset. Instead we found widespread obliterative bronchiolitis (OB) and signs of acute pulmonary rejection. Early-stage OB was present together with CMV pneumonitis in the patient who had survived transplantation for 2 months. The cause of death in the remaining patient was a bacterial superinfection of the chronic CMV pneumonitis still present more than 1 year after its first manifestation. There were no signs of OB. The marked differences in the clinical course and histologic presentation of CMV pneumonitis in heart-lung transplant recipients and its high, but not uniform, association with OB emphasize the complex interrelations between viral infections and pulmonary rejection.

Adult↗
PubMed1990

The effects of L-vesamicol, an inhibitor of vesicular acetylcholine uptake, on two populations of miniature endplate currents at the snake neuromuscular junction.

The actions of the active L-isomer of vesamicol, an inhibitor of the vesicular storage of acetylcholine, has been studied on spontaneous and evoked acetylcholine release at the snake neuromuscular junction. Miniature endplate currents and endplate currents were recorded from cut muscle fibres of the garter snake, Thamnophis sirtalis. In controls, prolonged periods of high frequency nerve stimulation produced a bimodal distribution of miniature endplate current amplitudes. The stimulation induced "small-mode" miniature endplate currents had a mean amplitude of around 40-55% of the pre-stimulation miniature endplate current. Relative to the normal-sized post-stimulation miniature endplate current, the proportion and, to a lesser extent, amplitude of the small-mode miniature endplate currents was related to both the frequency and duration of nerve stimulation and to the extracellular calcium ion concentration. In unstimulated preparations, L-vesamicol (2-5 microM) did not affect either endplate current quantal content or miniature endplate current amplitude or frequency. However, at these doses, the mean amplitude of the stimulation-induced, small-mode miniature endplate current was reduced by L-vesamicol in a concentration-dependent manner such that they were not visible at the highest dose. L-Vesamicol had no affect on the mean or coefficient of variance of amplitude of the larger, normal-sized miniature endplate current. Additionally, the stimulation-induced increase in overall miniature endplate current frequency seen in controls was abolished by 5 microM L-vesamicol. After prolonged 10 Hz nerve stimulation endplate current amplitude was markedly reduced in both controls (by 94%) and in the presence of 5 microM L-vesamicol (by 98%). Analysis of endplate current amplitude variance showed that in control the decrease was due to reductions in both quantal content and quantal size while in L-vesamicol the decrease was due entirely to a change in quantal content with no change in quantal size. Thus, we have observed that L-vesamicol selectively reduces the amplitude of a population of stimulation-induced small-mode quanta both as miniature endplate currents and as constituents of endplate currents. We suggest that these quanta are derived from a highly active, readily releasable pool. An action of L-vesamicol on this labile pool is consistent with previous observations on its ability to inhibit the vesicular storage of acetylcholine.

Acetylcholine↗
PubMed1990

End-plate ion channel block produced by lincosamide antibiotics and their chemical analogs.

Five lincosamide compounds were studied for their effects on end-plate currents (epcs), miniature end-plate currents and acetylcholine-induced current fluctuations in the garter snake costocutaneous nerve-muscle preparation. At high concentrations, lincomycin and clindamycin reduced epc amplitude, but analysis of driving functions showed that only with clindamycin was this due solely to changes in epc quantal content. The effect of lincomycin on epc amplitude was exaggerated by rapid channel block during the rising phase of the epc. Clindamycin produced currents with a single exponential decay and single Lorentzian noise spectra. All the other compounds produced currents which decayed as the sum of two exponential components. For lincomycin and epilincomycin, noise spectra consisted of two Lorentzian components. For epiclindamycin and deoxylincomycin, although epcs and miniature end-plate currents decayed with two components, it was not possible to separate two components in the noise spectra. A kinetic analysis of ion channel blocking actions showed only small differences between the two pairs of stereoisomers studied. End-plate ion channel blocking and unblocking rate constants did not vary greatly among the compounds but the end-plate ion channel unblocking rate constant values for the two lincomycin stereoisomers were larger than those for the two clindamycin stereoisomers. Deoxylincomycin exhibited properties similar to those of the clindamycins. It was concluded that lipid solubility, not stereochemical conformation, plays the greater role in determining the ion channel blocking properties within the series, particularly that of the rate of dissociation of the compound from end-plate ion channels.

Animals↗
PubMed1990

Lavage versus serum measurements of lysozyme, angiotensin converting enzyme and other inflammatory markers in pulmonary sarcoidosis.

The aim of this study was to explore whether amounts of angiotensin converting enzyme (ACE) and lysozyme produced within the lungs correlate more closely than serum levels of these enzymes, or other inflammatory markers, with chest radiographic profusion scores, lung function and therapy response in patients with pulmonary sarcoidosis. We have studied 25 patients, and levels in bronchoalveolar lavage (BAL) were used to determine "local" enzyme production by reference to serum and lavage albumin. Before treatment, serum lysozyme levels were elevated in more patients (80%) than serum ACE levels (40%). They also gave the best overall correlation with clinical measurements prior to treatment and falls in serum lysozyme closely parallelled improvement in lung function (transfer factor for carbon monoxide (DLCO)) on therapy. The only other markers showing significant correlations with disease severity were lavage neutrophil counts per ml and "local" ACE measurements prior to treatment. The value of pre-treatment levels of the different inflammatory markers in predicting response to corticosteroid therapy was explored and the only significant finding was that BAL lymphocyte percentages and numbers.ml-1 were initially higher in patients with lower post-treatment chest X-ray scores (p less than 0.01 and p less than 0.05, respectively). We conclude that serum lysozyme levels appear to be a more useful marker of overall disease activity in sarcoidosis than measurements of other inflammatory markers. However, BAL lymphocyte counts were the best predictive marker of radiographic response to corticosteroids.

Adult↗
PubMed1990

[The prognostic value of Jass' histopathological classification of cancer of the left colon and rectum].

Histological material from 121 patients who underwent surgery for cancer of the left colon and rectum was reexamined by two pathologists according to criteria put forward in Jass' histopathological classification. A prevalence of Jass' grades II (36.4%) and III (47.9%) were observed in this series. There was no correlation between the site of neoplasia but there was a clearly increased incidence of advanced stages C and D according to Dukes-Kirklin's classification within Jass' grades II, III and IV (p less than 0.005) and growth pattern, but not for the configuration of tubules. The new histopathological model proved to be more reliable in prognostic terms in the case of cancer of the rectum compared to that of the left colon, but at present its clinical significance is limited to specifying the site and stage of the neoplasia. The latter was found to be the most reliable prognostic parameter.

Adenocarcinoma↗