Biomedical subjects
Publications and source records attributed to Martin Wilson.
The protein Bassoon is found in the cytoskeletal matrix at the active zone of conventional synapses and in presynaptic ribbons of photoreceptor synapses. Two new studies in Neuron show that Bassoon's most prominent role at conventional synapses is to enable vesicle cycling, whereas, in photoreceptors it attaches the ribbon to the presynaptic membrane.
Rod bipolar cells in the mammalian retina receive synaptic input from many noisy rod photoreceptors. When photons are scarce, linear addition of inputs would swamp signals with noise. A nonlinearity at the synapse optimizes the signal to noise ratio.
BACKGROUND: The therapeutic benefits that accompany the continuous administration of organic nitrates are attenuated by the development of tolerance to the compounds. Altered superoxide production and NO bioavailability have been implicated in contributing to the development of tolerance, an effect that may be ameliorated by the administration of antioxidants. METHODS AND RESULTS: We studied the effect of 3 days of continuous transdermal administration of nitroglycerin (NTG) (10 mg/24 hours) on platelet free radical (NO and superoxide anion [O2*-] activity) with and without coadministration of supplemental ascorbate (2.4 g/24 hours). NAD(P)H oxidase activity, nitric oxide synthase (NOS) activity, and cyclic guanosine monophosphate (cGMP) content were also assessed. Radial artery pressure pulse waveforms were used to track the hemodynamic actions of NTG. Three days of NTG/placebo was associated with a significant increase in platelet NO and O2*- production from 1.0+/-1.17 to 2.52+/-0.88 pmol/10(8) platelets and 13.2+/-4.8 to 72.5+/-34.4 pmol/10(8) platelets, respectively (P<0.01 for both). These changes were accompanied by increased platelet NADH oxidase activity from 47.9+/-11.0 to 65.3+/-13.6 pmol O2*- min/mg protein and cGMP content from 0.60+/-0.10 to 0.89+/-0.16 pmol/10(9) platelets (P<0.05 for both). Administration of NTG/ascorbate attenuated both NO and O2*- release in platelets. CONCLUSIONS: Three days of continuous transdermal administration of NTG was accompanied by increased platelet NO and O2*- production and NADH oxidase activity that was suppressed by coadministration of oral ascorbate. Although a significant degree of tolerance would be expected during continuous nitrate administration, a residual hemodynamic action could be identified by arterial pulse contour analysis.
Quantitative diffusion-weighted MRI has been applied to the study of neurological diseases, including multiple sclerosis, where the molecular self-diffusion coefficient D has been measured in both lesions and normal-appearing white matter. Histograms of D have been used as a novel measure of the "lesion load", with potential applications that include the monitoring of efficacy in new treatment trials. However different ways of measuring D may affect its value, making comparison between different centres and research groups impossible. We aimed to assess the effect, if any, of using two different MRI sequences on the value of D. We studied 13 healthy volunteers, using two different quantitative diffusion sequences (including different b(max) values and gradient applications). Maps of D were analysed using both regions of interest (ROI) in white matter and "whole brain" histograms, and compared between the two sequences. In addition, we studied three standardised test liquids (with known values of D) using both sequences. Histograms from the two sequences had different distributions, with a greater spread and higher peak position from the sequence with lower b(max). This greater spread of D was also evident in the white matter and test liquid ROI. "Limits of agreement" analysis demonstrated that the differences could be clinically relevant, despite significant correlations between the sequences obtained using simple rank methods. We conclude that different quantitative diffusion sequences are unlikely to produce directly comparable values of D, particularly if different b(max) values are used. In addition, the use of inappropriate statistical tests may give false impressions of close agreement. Standardisation of methods for the measurement of D are required if these techniques are to become useful tools, for example in monitoring changes in the disease burden of multiple sclerosis.
T(1) relaxation time (T(1)) is a quantitative magnetic resonance measure that enables a global evaluation of white matter disease in multiple sclerosis (MS). We aimed to investigate whether mapping of T(1) values in critical white matter tracts, defined by diffusion tensor (DT) imaging, could provide a stronger surrogate marker of disability. 25 patients with relapsing-remitting MS and 14 healthy controls were imaged with a dual-echo T(2)-weighted sequence. Whole brain T(1) maps were acquired using a multi-slice inversion recovery sequence and DT images generated from a spin-echo, echo-planar diffusion weighted sequence. Trajectories were defined to follow the course of white matter fibre tracts in the pyramidal pathways and corpus callosum. T(1) values were sampled along these trajectories. Total white matter T(1) was sampled by defining white matter masks on axial slices of the T(1) maps. Median T(1) in the pyramidal tracts, corpus callosum and total white matter of MS patients was significantly longer than in controls (p < 0.0001). Median pyramidal tract T(1) correlated significantly with the pyramidal Kurtzke Functional Systems Score (r = 0.64, p = 0.0007) and the Expanded Disability Status Scale (r = 0.55, p = 0.005). By contrast, no correlation with disability was observed for corpus callosum T(1) or total white matter T(1). Our findings show that quantifying pathology within the pyramidal tracts, by utilizing T(1), provides a strong correlate of disability compared with the overall white matter burden of disease. Pyramidal tract T(1) may also provide an objective, sensitive measure for monitoring the progression of motor deficits and disability.
We have previously shown that disabling forward-mode Na(+)-Ca(2+) exchange in amacrine cells greatly prolongs the depolarization-induced release of transmitter. To investigate the mechanism for this, we imaged [Ca(2+)](i) in segments of dendrites during depolarization. Removal of [Na(+)](o) produced no immediate effect on resting [Ca(2+)](i) but did prolong [Ca(2+)](i) transients induced by brief depolarization in both voltage-clamped and unclamped cells. In some cells, depolarization gave rise to stable patterns of higher and lower [Ca(2+)] over micrometer-length scales that collapsed once [Na(+)](o) was restored. Prolongation of [Ca(2+)](i) transients by removal of [Na(+)](o) is not due to reverse mode operation of Na(+)-Ca(2+) exchange but is instead a consequence of Ca(2+) release from endoplasmic reticulum (ER) stores over which Na(+)-Ca(2+) exchange normally exercises control. Even in normal [Na(+)](o), hotspots for [Ca(2+)] could be seen following depolarization, that are attributable to local Ca(2+)-induced Ca(2+) release. Hotspots were seen to be labile, probably reflecting the state of local stores or their Ca(2+) release channels. When ER stores were emptied of Ca(2+) by thapsigargin, [Ca(2+)] transients in dendrites were greatly reduced and unaffected by the removal of [Na(+)](o) implying that even when Na(+)-Ca(2+) exchange is working normally, the majority of the [Ca(2+)](i) increase by depolarization is due to internal release rather than influx across the plasma membrane. Na(+)-Ca(2+) exchange has an important role in controlling [Ca(2+)] dynamics in amacrine cell dendrites chiefly by moderating the positive feedback of the Ca(2+) amplifier.