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Biomedical subjects

M J Peters

Publications and source records attributed to M J Peters.

At least 55 records · Page 3Linked to original sources
PubMed1995

Effects of glucocorticoids on transcription factor activation in human peripheral blood mononuclear cells.

Glucocorticoids have an inhibitory effect on inflammatory and immune responses, and this may be through the modulation of transcription factor binding to DNA. The interaction of the transcription factors, activator protein-1 (AP-1), nuclear factor kappa B (NF kappa B), and cAMP-responsive element binding protein (CREB) with DNA and glucocorticoid receptors (GR) was analyzed in human peripheral blood mononuclear cells by gel mobility shift assays. TNF-alpha, IL-1 beta and phorbol myristate acetate (PMA) treatment increased AP-1 and NF kappa B DNA binding by up to 200% but decreased CREB binding (38%) over a 60-min time course. Dexamethasone produced a rapid and sustained increase in glucocorticoid response element binding and a concomitant 40-50% decrease in AP-1, NF kappa B, and CREB DNA binding that was blocked by combined dexamethasone and cytokine or PMA treatment. These latter effects were due to increases in the nuclear localization of GR, not to reduced amounts of the other transcription factors. This suggests that in these cells GR within the nucleus interacts with cytokine-stimulated transcription factors by the process of cross coupling. This may be an important molecular site of steroid action.

Base Sequence↗
PubMed1995

Reduced dose salbutamol in comparison with standard dosage for symptom relief in asthma.

Regular treatment with beta 2-agonists has been reported to be associated with an increase in risk of asthma death or near death, and with a deterioration in asthma symptom control. Low-dose beta 2-agonists provide effective bronchodilatation and bronchoprotection, even though maximal bronchodilatation is not achieved, and they may offer a better safety profile. In a double-blind, randomized,, cross-over study, we evaluated the efficacy of low-dose salbutamol metered-dose inhaler (50 micrograms.puff-1), used over a period of 2 weeks, compared with a standard dose (100 micrograms.puff-1) in control of asthma symptoms in 20 moderately severe asthmatic subjects using inhaled glucocorticosteroid therapy. Asthma control was assessed by symptom scores, peak flow rates, spirometry, inhaler usage and, where possible, by bronchial responsiveness to methacholine. Despite a 46% reduction in mean weekly salbutamol dosage, mean forced expiratory volume in one second (FEV1), morning and evening peak expiratory flow (PEF), PEF variability, dose of methacholine provoking a 20% decrease in FEV1 (PC20) (n=9), and symptom scores showed no difference between low-dose and standard inhaler treatment periods. Low-dose inhaler administration resulted in a small but significant increase in number of inhaler actuations. Low-dose salbutamol metered-dose inhaler may, thus, be useful for control of symptoms in moderately severe asthma. This strategy could be used to achieve a reduction in total beta 2-agonist usage, which may minimize any potential for adverse effects.

Administration, Inhalation↗
PubMed1994

The effects of glucocorticoids on phorbol ester and cytokine stimulated transcription factor activation in human lung.

Glucocorticoids have a wide variety of effects which result in the dampening of inflammatory and immune responses and other challenges to homeostasis. An important site of steroid action may be on the control of transcription factor binding to DNA. The interaction of the transcription factors, activator protein 1 (AP-1) and nuclear factor kappa from B cells (NF kappa B) with DNA and glucocorticoid receptors was analysed by gel mobility shift assays following stimulation by tumour necrosis factor alpha (TNF alpha) and a phorbol ester (PMA) that activates protein kinase C. PMA and TNF alpha both caused significant (180-340%) increases in AP-1 and NF kappa B DNA binding which peaked at 15 minutes and decreased to a constant elevated level at between 1-3 hrs and was sustained for 24hrs. Dexamethasone (1 microM) caused a rapid and long lasting 40-50% decrease in both AP-1 and NF kappa B DNA binding lasting over 24hrs. Combined treatment with dexamethasone and PMA or TNF alpha prevented the increase in both AP-1 and NF kappa B binding due to PMA and TNF alpha returning levels to those seen in control untreated samples. This suggests that in human lung, the glucocorticoid receptor functionally interacts within the nucleus with other transcription factors that are induced by inflammatory mediators such as cytokines. This may be an important molecular site of steroid action in chronic inflammatory lung diseases such as asthma.

Adolescent↗
PubMed1994

Rifampicin in pneumococcal meningoencephalitis.

The cases are reported of two infants with pneumococcal meningitis in whom initial antibiotic treatment was ineffective despite the organisms being sensitive to the drugs used. A clinical and radiological diagnosis of meningoencephalitis was made. A rapid improvement followed the addition of rifampicin treatment.

Anti-Bacterial Agents↗
PubMed1993

Topography and source analysis of brain activity associated with selective spatial attention and memory search.

We investigated the topographical aspects of the ERP reflections of visual spatial attention and memory search. Spatial attention was found to enhance the amplitudes of the P1 and N1 deflections. The brain activity in the P1-N1 latency range could be modeled with a single moving equivalent dipole, or alternatively with two stationary dipoles in a spatio-temporal dipole model. The dipoles were located in mesial and lateral posterior brain regions. Similar dipole solutions were obtained for ERPs to attended and unattended stimuli. Increasing the memory search requirements of the task resulted in an increase of late negativity, which was topographically distinguishable from the P3 component.

Attention↗
PubMed1993

Processing MRI data for electromagnetic source imaging.

Estimation of the source of activity in the brain from electro- and magneto-encephalographic measurements is becoming increasingly common. Structural information could assist in improving the calculation of the sources as well as providing the context of the source location. Magnetic resonance images are very useful for this purpose, but they still need to undergo various processing steps. The paper describes in detail a practical method for full automatic processing of MRI images of a head, including segmentation of the images and triangulation of the surfaces.

Brain↗
PubMed1993

A comparison of different numerical methods for solving the forward problem in EEG and MEG.

In view of the complexity of the conductivity and the geometry of the human head, a numerical method would appear to be necessary for the adequate calculation of the electric potential and the magnetic induction generated by electric sources within the brain. Four numerical methods that could be used for solving this problem are the finite-difference method, the finite-element method, the boundary-element method, and the finite-volume method. These methods could be used to calculate the electric potential and the magnetic induction directly. Alternatively, they could be applied to the electric potential or the electric field and the magnetic induction could then be determined by numerical integration of the Biot-Savart law. In this paper the four numerical methods are briefly reviewed. Thereafter the relative merits of the methods and the various options for using them to solve the EEG and MEG problem are evaluated.

Brain Mapping↗
PubMed1993

A fast method to compute the potential in the multisphere model.

A series expansion is derived for the potential distribution, caused by a dipole source in a multilayered sphere with piecewise constant conductivity. When the radial coordinate of the source approaches the radial coordinate of the field point the spherical harmonics expansion converges only very slowly. It is shown how the convergence can be improved by first calculating an asymptotic approximation of the potential and using the so-called addition-subtraction method. Since the asymptotic solution is an approximation of the true solution, it gives some insight on the dependence of the potential on the conductivities. The formulas will be given in Cartesian coordinates, so that difficulties with coordinate transformations are avoided. Attention will be paid to the (fast) computation of the partial derivatives of the potential, which is useful for inverse algorithms.

Algorithms↗
PubMed1992

Effects of inhalation of N-formyl-methionyl-leucyl-phenylalanine in the well elderly and in patients with chronic bronchitis.

BACKGROUND: Inhalation of the bacterial peptide N-formyl-methionyl-leucyl-phenylalanine (FMLP) produces bronchoconstriction in normal subjects. FMLP thus has a putative role as a mediator of bronchoconstriction associated with bacterial bronchial infection. METHODS: The effects of FMLP inhalation were examined in ten subjects with a history of chronic bronchitis and ten age matched control subjects. Each subject inhaled FMLP doses from 0.025 to 0.8 mumol to determine the provocative dose of FMLP causing a 20% fall in FEV1(PD20FMLP). FEV1 was recorded every five minutes after the final FMLP inhalation until it had returned to 95% of baseline FEV1 or 60 minutes had elapsed. The time to return to 95% baseline FEV1 was recorded or extrapolated from the recovery curve as an index of rapidity of recovery. Total and differential white cell counts were performed on each subject at baseline and five and 15 minutes after the final FMLP inhalation. RESULTS: The geometric mean PD20 FMLP in the patients with chronic bronchitis was 0.06 mumol (95% confidence interval 0.015-0.26), which was significantly lower than that in the control subjects (0.21 mumol (0.02-1.9)). PD20 FMLP in the patients with chronic bronchitis but not age matched controls (p = 0.35) was lower than that found previously in young normal subjects (0.35 mumol (0.07-1.8). The return to 95% baseline FEV1 occurred after 86(10) minutes in subjects with chronic bronchitis and in 81(23) minutes in their age matched controls, in both cases being much slower than that seen in young subjects (29(9) minutes). CONCLUSION: Patients with chronic bronchitis may be especially susceptible to formyl peptides elaborated by bacteria during bacterial bronchial infection.

Administration, Inhalation↗
PubMed1992

Haematological effects of inhalation of N-formyl-methionyl-leucyl-phenylalanine in man.

BACKGROUND: N-Formyl-methionyl-leucyl-phenylalanine (FMLP) is a bacterial oligopeptide which stimulates neutrophil chemotaxis, degranulation and superoxide generation. Inhalation of FMLP produces bronchoconstriction in man; in the rabbit this is in part neutrophil dependent. The effects of inhalation of FMLP on peripheral blood leucocytes in normal subjects has been studied. METHODS: This was an open study in non-asthmatic subjects. Change in total peripheral white cell count were studied for 15 minutes after inhalation of 0.4 mumol FMLP in six subjects. Change in total and differential white cell count and spontaneous neutrophil chemiluminescence were then studied five and 30 minutes after inhalation of 0.4 mumol FMLP (n = 7) or diluent (n = 4). Finally, leucocytes from three subjects were labelled ex vivo with technetium-99m labelled sulphur colloid and reinfused. The effect of inhalation of FMLP or diluent on pulmonary neutrophil flux was studied by continuous gamma scanning of a pulmonary window. RESULTS: Leucopenia occurs rapidly after inhalation of FMLP, the nadir of the white cell count (53% of baseline) occurring at four minutes. This was followed by a rebound increase in white cell count evident at 15 minutes (154% of baseline). Five minutes after inhalation of 0.4 mumol FMLP, neutropenia (17% of baseline) and monocytopenia (40% of baseline) were seen followed again by a neutrophilia (213% of baseline at 30 minutes). The eosinophil count was significantly reduced at 30 minutes (24% of baseline). Neutrophil chemiluminescence was elevated (186% of baseline) at the time of the neutropenia. There was no influx of labelled cells to the lung during the period of neutropenia. CONCLUSION: FMLP inhalation activates circulating leucocytes. In vivo production of FMLP in the airway could contribute to bronchial inflammation during bacterial infection.

Administration, Inhalation↗
PubMed1991

Source localization of EEG versus MEG: empirical comparison using visually evoked responses and theoretical considerations.

Theoretically, the information we can obtain about the functional localization of a source of brain activity from the scalp, for instance evoked by a sensory stimulus, is the same whether one uses EEG or MEG recordings. However, the nature of the sources and, especially of the volume conductor, poses constraints such that appreciable differences between both types of data may exist. We present here empirical and theoretical data that illustrate which are the main constraints and to what extent they may affect electric potential and magnetic field maps. The empirical data consists of visual evoked potential and magnetic fields to the appearance of a checkerboard pattern (half-visual field stimulation). The concept of equivalent dipole is presented and its limitations are discussed. It is considered that the concept of equivalent dipole (ED) yields only an approximate description of the activity of a patch of cortex. A main difference between EEG and MEG recordings is the fact that radially oriented dipoles can hardly be seen in the MEG in contrast with the EEG. Accordingly, a weak tangential dipole component is difficult to distinguish in the EEG if a strong radial component is also present. However, a combination of both methods can give useful complementary information in such cases. A factor that influences largely such differences is the model of volume conductor used. A four concentric spheres model, as commonly used for solving the inverse problem of source localization, causes appreciable errors when EEG data are used but much less in case of the MEG. The use of a model consisting of eccentric spheres fitting the four compartments, brain, CSF, skull and scalp, provides a better approximation of the real geometry of the head and allows to obtain comparable results for visual evoked potentials and magnetic fields. It is emphasized that for precise localization of EDs, especially based on EEG recordings, a realistic model of the different compartments of the head is necessary. The latter must be tailor made to a given subject using MRI-scans, in view of the large variability in head geometry between subjects.

Adult↗
PubMed1991

The use of the asymptotic expansion to speed up the computation of a series of spherical harmonics.

When a function is expressed as an infinite series of spherical harmonics the convergence can be accelerated by subtracting its asymptotic expansion and adding it in analytically closed form. In the present article this technique is applied to two biophysical cases: to the potential distribution in a spherically symmetric volume conductor and to the covariance matrix of biomagnetic measurements.

Brain↗
PubMed1991

Effect of neutral endopeptidase inhibition of f-Met-Leu-Phe-induced bronchoconstriction in the rabbit.

Inhalation of f-Met-Leu-Phe (FMLP) produces dose-dependent increases in pulmonary resistance (RL) in rabbits. We hypothesized that inhibition of neutral endopeptidase (NEP), which has high affinity for FMLP, would augment the response to FMLP inhalation. We found the increase in RL above baseline in response to FMLP to be reduced from 56 +/- 18 to 8 +/- 10% (P less than 0.01) by phosphoramidon (1 mg/kg) and to 15 +/- 6% (P less than 0.02) by thiorphan (3 mg/kg). The geometric mean dose of FMLP producing a 20% rise in RL (PC20RL FMLP) was increased by phosphoramidon from 1.1 to 4.5 mg/ml (P less than 0.05). Enkephalins, which are also NEP substrates, modulate cholinergic neurotransmission in the airway. Inhibition of the FMLP response by phosphoramidon was reversed by coadministration of naloxone (0.1 mg/kg); after atropine (2 mg/kg) the change in RL in response to FMLP was reduced to 7 +/- 4% (P less than 0.01), whereas morphine (0.15 mg/kg) increased PC20RL FMLP to 5.1 mg/ml (P less than 0.05). FMLP-induced bronchoconstriction in the rabbit is vagally mediated, and reduced responses after NEP inhibition may reflect modulation of cholinergic bronchoconstriction by enkephalins. Changes in airway NEP activity may influence the activity of a wide range of its substrates, of which some are bronchoconstrictors and others bronchodilators.

Airway Resistance↗
PubMed1991

Effects of prolonged inhalation of N-formyl-methionyl-leucyl-phenylalanine in rabbits.

On the basis of its potent proinflammatory and spasmogenic effects, N-formyl-methionyl-leucyl-phenylalanine (FMLP), a bacterial oligopeptide, is a putative mediator of bronchoconstriction and airway inflammation during bacterial bronchial infection. However, after an FMLP dose-response curve in rabbits, tachyphylaxis to a second challenge was seen in some rabbits and airway inflammation was absent. This study was designed to reproduce the more prolonged airway exposure to FMLP that may occur during bacterial infection. Two groups of rabbits received FMLP [5 mg/ml in 66% dimethyl sulfoxide- (DMSO) saline] or DMSO diluent alone by nebulization every 15 min for 2 h. Pulmonary resistance (RL) was measured at 1 and 2 h. Recovery from bronchoconstriction was also assessed by measuring RL every 30 min for 2 h after the final FMLP administration. Sections of trachea and large bronchi were prepared and graded by quadrant from 0 to 3 for inflammation, a total score from 0 to 12 being given for each section. There was a progressive increase in RL in FMLP-treated rabbits, reaching 68 +/- 9% above baseline after 120 min, a significantly greater change than after diluent, 8 +/- 12% (P less than 0.01). RL remained elevated above baseline for 90 min after the final FMLP dose. Inflammation scores were greater after FMLP than DMSO: 9.3 +/- 0.5 vs. 4.3 +/- 0.7 (P less than 0.01) in trachea and 5.2 +/- 0.4 vs. 1.7 +/- 0.5 (P less than 0.01) in lobar bronchi. We conclude that prolonged exposure of airways to FMLP produces a sustained increase in RL and airway inflammation, the cardinal features of infective exacerbations of chronic airflow limitation.

Administration, Inhalation↗