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Biomedical subjects

David Parker

Publications and source records attributed to David Parker.

At least 37 records · Page 2Linked to original sources
PubMed2005

Sonographically guided core biopsy in the assessment of thyroid nodules.

PURPOSE: This study was conducted to assess the value of sonographically guided core biopsy in the evaluation of thyroid nodules by comparison with fine-needle aspiration cytology (FNAC) performed with and without sonographic guidance. METHODS: We performed a retrospective analysis of a consecutive series of 645 thyroid samples obtained at a single center. Samples came from 422 patients who underwent FNAC (with or without sonographic guidance), sonographically guided core biopsy, or excision of thyroid tissue with or without prior frozen sectioning. Final diagnoses were obtained from surgery or clinical follow-up. Initial and final diagnoses were compared. RESULTS: Adequate samples for assessment were obtained in 87% of core biopsies, compared with 60% of cytology aspirates (p <0.001). Sonographically guided core biopsy and sonographically guided FNAC both had zero false-negative rates for the diagnosis of malignancy, compared with a 7.0% false-negative rate (95% confidence interval, 2.0-12.0%) for aspiration cytology when sonography was not used. With core biopsy, 11% of patients required surgical confirmation of the diagnosis, compared with 43% of patients following FNAC (p <0.001). There were no major complications following core biopsy. CONCLUSIONS: Sonographically guided core biopsy provides an accurate and safe alternative to FNAC in the assessment of thyroid nodules.

Adenocarcinoma, Follicular↗
PubMed2005

Pharmacological approaches to functional recovery after spinal injury.

Locomotion results from the activity in neural networks in the spinal cord that together with sensory and descending inputs generate coordinated motor outputs. Descending inputs include glutamatergic, monoaminergic, and peptidergic pathways. Spinal injuries interrupt these descending pathways, resulting in the disruption or loss of function. Drugs that target these endogenous transmitter systems have been used to improve function after spinal injury. However, individual drugs can have beneficial or deleterious effects in different studies and thus there is little consensus on optimal pharmacological strategies. The variability may be influenced by changes introduced by the type of lesion (complete or partial), time after injury, or the lack of specific ligands that target specific transmitter systems. It is now recognised that these transmitter systems do not necessarily act in isolation, but can interact to evoke additive, inhibitory, or novel metamodulatory effects. Meta interactions mean that differing chemical environments in lesioned spinal cords could influence drug effects. The spinal cord also exhibits injury-induced changes, which could alter the chemical environment and functional properties over time. While they have not been considered in pharmacological approaches to spinal injury, interactive and adaptive changes could influence the effects of spinal lesions and therapeutic interventions. The properties of endogenous transmitter systems in spinal locomotor networks before and after spinal lesions need to be understood, and pharmacological tools that target specific functional aspects need to be developed.

Adrenergic Agents↗
PubMed2004

Metaplastic facilitation and ultrastructural changes in synaptic properties are associated with long-term modulation of the lamprey locomotor network.

The neuropeptide substance P evokes a long-term protein synthesis-dependent increase in the cycle frequency of locomotor network activity in the lamprey. Although cellular and synaptic mechanisms that could induce this effect have been identified, nothing is known of the underlying maintenance mechanisms. These mechanisms have been examined here. Substance P potentiates low-frequency-evoked EPSPs from excitatory network interneurons. It also converts the depression of the EPSP during spike trains into facilitation, an example of metaplasticity. The metaplasticity was associated with a reduction of the transmitter release probability but an increase in the number of release sites. Although the potentiation of low-frequency-evoked EPSPs recovered within 1 hr, the metaplastic facilitation had not recovered 3-4 hr after substance P application. The metaplasticity thus extended into the protein synthesis-dependent maintenance phase of the network modulation, making it the only identified cellular or synaptic effect of substance P to last this long. It also had the same induction and maintenance features as the network burst frequency modulation, further suggesting that the two effects were related. Long-term changes in synaptic properties are often associated with changes in synaptic organization. We have thus also examined the effects of substance P on synaptic ultrastructure up to 5 hr after substance P application. Substance P had several significant effects. These included an increase in the number of docked vesicles and a reduction of the synaptic gap. Substance P thus has long-term effects on synaptic organization and function. The relevance of these effects to the long-term locomotor network modulation is discussed.

Animals↗
PubMed2004

NMR and chiroptical examination of the diastereoisomers of (S)-Eu-EOB-DTPA.

The solution structure of the diastereoisomers of (S)-Eu--EOB--DTPA has been analysed by (1)H NMR, CD and CPL spectroscopy. Two major species exist which possess very similar (1)H NMR paramagnetic shifts and emission spectra, consistent with a 9-coordinate structure involving one bound water. Circularly polarised luminescence data are consistent with a common Lambda-helicity for each isomer; the isomers differ only in the absolute configuration of the central nitrogen atom.

Journal Article↗
PubMed2004

Design, synthesis and evaluation of ratiometric probes for hydrogencarbonate based on europium emission.

A series of cationic, zwitterionic and anionic macrocyclic europium complexes has been prepared incorporating a N or C- linked acridone chromophore that allows sensitisation of Eu emission following excitation at 390-410 nm. Each of these complexes selectively binds bicarbonate at physiological pH and reversible binding is signalled by a change in the form and relative intensity of the Eu emission spectrum. Affinity for bicarbonate is regulated by overall complex charge and falls within the range required for intracellular or extracellular analyses. Monitoring the ratio of the intensity of Eu emission at up to three wavelengths, e.g. 618/588 or 618/702 nm allows the solution concentration of bicarbonate to be deduced in a background of competing anions such as lactate, citrate and phosphate. Preliminary screens reveal the complexes to be non-toxic to NIH-3T3 cells and to be taken inside the cell, encouraging further study.

Acridines↗
PubMed2004

Steric control of lanthanide hydration state: fast water exchange at gadolinium in a mono-amide 'DOTA' complex.

Detailed analyses of the solution structure and exchange dynamics of two sets of homologous mono-amide triacetate lanthanide complexes (Ln = Eu, Gd) of cyclen have been undertaken. The complex [LnL1], bearing an N-linked CH2CH2NHCO-pyridyl moiety, forms mono-aqua (q = 1) species in solution and the Gd complex undergoes rapid water exchange (k(ex)= 11 x 10(7) s(-1), 298 K) as a result of the steric destabilisation of the Ln-water binding interaction. The homologous complex with a C-3 spacing chain, [LnL2], forms a q = 0 species.

Journal Article↗
PubMed2004

Stereocontrol in organic synthesis using silicon-containing compounds. Studies directed towards the synthesis of ebelactone A.

Several approaches to the synthesis of ebelactone A 2 are described, culminating in the synthesis of the benzenesulfonate of 2-epi-ebelactone A 161. All the approaches were based on three fragments A, B and C, originally defined in general terms in, but eventually used as the aldehyde 72, the allenylsilane 3 and the aldehyde 139, respectively. They were joined, first B with C, and then B+C with A. In the main routes to fragments A and C, the relative stereochemistry was controlled by highly stereoselective enolate methylations 67-->67, 68-->69, and 135-->136, in each case anti to an adjacent silyl group, and by a highly stereoselective hydroboration of an allylsilane 137-->138, also anti to the silyl group. The hydroxyl groups destined to be on C-3 and C-11 were unmasked by silyl-to-hydroxy conversions 69-->70 and 138-->139 with retention of configuration. The stereochemistry created in the coupling of fragment B to C was controlled by the stereospecifically anti S(E)2' reaction between the enantiomerically enriched allenylsilane 3 and the aldehyde 139. The double bond geometry was controlled by syn stereospecific silylcupration 148-->151, and preserved by iododesilylation 151-->152 of the vinylsilane with retention of configuration, and Nozaki-Hiyama-Kishi coupling with the aldehyde 72 gave the whole carbon skeleton 153 of ebelactone A with the correct relative configuration, all of which had been controlled by organosilicon chemistry. In the steps to remove the superfluous allylic hydroxyl, an intermediate allyllithium species 156 abstracted the proton on C-2, and its reprotonation inverted the configuration at that atom. Other routes to the fragments A and C were also explored, both successful and unsuccessful, both silicon-based and conventional, and a number of unexpected side reactions were investigated.

Journal Article↗
PubMed2004

Excitement in f block: structure, dynamics and function of nine-coordinate chiral lanthanide complexes in aqueous media.

Lanthanide complexation chemistry has been studied intensively over the past 15 years and progress has been stimulated by the advent of well-defined, kinetically robust systems tailored to applications as bioactive probes for magnetic resonance and luminescence. In this tutorial review, the extent to which an enhanced understanding of the relationship between complex structure and spectral properties is emerging is discussed, together with an examination of the mechanism of ligand exchange processes. Such issues are aiding the development of responsive probes, ranging from simple sensors to more complex studies defining water structure and exchange dynamics.

Animals↗
PubMed2003

Structural analysis of nine-coordinate lanthanide complexes: steric control of the metal-water distance across the series.

The structures of 10 isomorphous lanthanide (Ln) complexes of a chiral DOTA tetra-amide ligand (L(1)), [LnL(1)(H(2)O)](CF(3)SO(3))(3).3H(2)O, crystallizing in space group P2(1), have been studied by single-crystal X-ray diffraction. The Ln coordination is a O(4)N(4) square antiprism, the O(4) base of which is capped by an aqua ligand. The sterically demanding position of the latter results in the lengthening of the Ln-OH(2) distance along the Pr to Lu series by 0.06 A (after allowing for the lanthanide contraction). In parallel, the distance between the bound water oxygen and the second-sphere water oxygen is reduced from 3.17 A (Pr) to 3.04 A (Lu), consistent with the enhanced hydrogen bond acceptor ability of the coordinated water oxygen across the series. A Cambridge Structural Database survey of [Ln(H(2)O)(9)](CF(3)SO(3))(3) salts (space group P6(3)/m) and of six reported isostructural complexes of DOTA [L(2)] revealed a similar trend. The implications of the resultant destabilization of the ground state structure for the water interchange process are discussed.

Journal Article↗
PubMed2003

Activity-dependent feedforward inhibition modulates synaptic transmission in a spinal locomotor network.

The analysis of synaptic properties in neural networks has focused on the properties of individual synapses. As a result, little is known of how neural assemblies arise from the connectivity and functional properties of different classes of network neurons. I examined synaptic properties in the lamprey locomotor network. Here I show that, in addition to their monosynaptic inputs to motor neurons, a proportion of the excitatory network interneurons (EINs) evoke an activity-dependent disynaptic feedforward inhibitory input. Connections from the excitatory interneurons to small ipsilateral inhibitory interneurons were found that could account for the feedforward inhibition. Both synapses in the disynaptic pathway exhibited activity-dependent facilitation during physiologically relevant spike trains, which could contribute to the delayed, activity-dependent development of the feedforward IPSP. Although it was not as common as the feedforward inhibition, the excitatory interneurons could also evoke feedforward excitatory inputs in motor neurons. EIN inputs to motor neurons usually depress during spike trains. In connections in which a delayed IPSP occurred, blocking the feedforward inhibition in motor neurons or preventing the activation of the disynaptic pathway abolished the depression of the direct EPSP during the spike train and could reveal an underlying facilitation. The feedforward inhibition thus heterosynaptically depressed the direct excitatory input to motor neurons. Activity-dependent heterosynaptic effects acting within network cellular assemblies can thus influence the integration of synaptic inputs in motor neurons. This could help to terminate ipsilateral motor neuron spiking during network activity.

Action Potentials↗
PubMed2003

Structural and NMR investigations of the ternary adducts of twenty alpha-amino acids and selected dipeptides with a chiral, diaqua-ytterbium complex.

A detailed investigation of the nature of the binding of each of the 20 common alpha-amino acids and various selected dipeptides to a chiral, diaqua-ytterbium complex in aqueous solution has been carried out. Analysis of the dipolar 1H NMR paramagnetic shifts suggests that the alpha-amino acids form a common chelated structure within a nine-coordinate mono-capped square antiprismatic coordination environment, with the amine N axially disposed. Crystal structures of nine chelated YbL1-amino acid adducts (Gly, Ala, Ser, Thr, Met) confirm this. The ternary complexes with dipeptides (e.g. Gly-Ala, Gly-Ser, Gly-Met, Gly-Asp, Gly-Asn, Gly-His, Ser-Met, Asp-Phe, His-Gly) also favour the terminal amine as the axial donor with the proximate amide group binding to generate a five-ring chelate. Evidence for chelation through side-chain functionality was found only in the case of N-terminal Asp. The chiral environment about the ytterbium ion upon amino acid binding has also been probed using near-IR circular dichroism spectroscopy.

Amino Acids↗
PubMed2003

Enantiopure lanthanide complexes incorporating a tetraazatriphenylene sensitiser and three naphthyl groups: exciton coupling, intramolecular energy transfer, efficient singlet oxygen formation and perturbation by DNA binding.

In cationic nine-coordinate chiral terbium and europium complexes incorporating exciton-coupled naphthyl groups and a tetraazatriphenylene sensitising chromophore, efficient intramolecular energy transfer occurs leading to population of the naphthyl triplet state. With the terbium complex, the absolute quantum yield of singlet oxygen formation is 51% (lambda(exc) 355 nm), and for the Eu complex the intensity of metal-based emission increases by up to 350% on binding to poly(dGdC) or calf-thymus DNA, and was greater for the delta-isomer.

Animals↗
PubMed2003

Ternary complexes between cationic GdIII chelates and anionic metabolites in aqueous solution: an NMR relaxometric study.

The (1)H and (17)O NMR relaxometric properties of two cationic complexes formed by Gd(III) with a macrocyclic heptadentate triamide ligand, L(1), and its Nmethylated analogue, L(2), have been investigated in aqueous media as a function of pH, temperature and magnetic field strength. The complexes possess two water molecules in their inner coordination sphere for which the rate of exchange has been found to be sensibly faster for the Nmethylated derivative and explained in terms of electronic effects (decrease of the charge density at the metal center) and perturbation of the network of hydrogen-bonded water molecules in the outer hydration sphere. The proton relaxivity shows a marked dependence from pH and decreases of about six units in the pH range 6.5 to 9.0. This has been accounted for by the displacement of the two water molecules by dissolved carbonate which acts as a chelating anion. The formation of ternary complexes with lactate, malonate, citrate, acetate, fluoride and hydrogenphosphate has been monitored by (1)H NMR relaxometric titrations at 20 MHz and pH 6.3 and the value of the affinity constant, K, and of the relaxivity of the adducts could be obtained. Lactate, malonate and citrate interact strongly with the complexes (log K > or =3.7) and coordinate in a bidendate mode by displacing both water molecules. Larger affinity constants have been measured for GdL(2). Acetate, fluoride and hydrogenphosphate form monoaqua ternary complexes which were investigated in detail with regard to their relaxometric properties. The NMR dispersion (NMRD) profiles indicate a large contribution to the relaxivity of the adducts from water molecules belonging to the second hydration shell of the complexes and hydrogen-bonded to the anion. A VT (17)O NMR study has shown a marked increase of the rate of water exchange upon binding which is explained by coordination of the anion in an equatorial site, thus leaving the water molecule in an apical position, more accessible for interactions with the solvent molecules of the second hydration shell which facilitate the exchange process.

Chelating Agents↗
PubMed2003

Variable properties in a single class of excitatory spinal synapse.

Although synaptic properties are specific to the type of synapse examined, there is evidence to suggest that properties can vary in individual synaptic populations. Here, a large sample of monosynaptic connections made by excitatory interneurons (EINs) onto motor neurons in the lamprey spinal cord locomotor network has been used to examine the properties of a single class of spinal synapse in detail. The properties and activity-dependent plasticity of EIN-evoked EPSPs varied considerably. This variability occurred at convergent inputs made by several EINs onto single motor neurons. This suggests that it was an intrinsic network property and not simply related to differences between animals or experiments. The activity-dependent plasticity of EIN-evoked EPSPs could be negatively or positively related to the initial EPSP amplitude (P1 and P2 connections, respectively). This reflected the development of facilitation and depression from either small or large initial EPSPs. To identify differences in presynaptic properties that could contribute to the synaptic variability, the quantal amplitude, release probability, number of release sites, and size of the available vesicle pool were examined. This analysis suggested that the variable amplitude and plasticity of EPSPs at P1 and P2 connections reflected an interaction between the release probability and the size of the available transmitter store. There is thus significant functional variability in EIN synaptic properties. Synapses ranged from strong (evoked postsynaptic spikes) to weak (small depressing EPSPs). The selection of interneurons with different synaptic properties could provide an intrinsic mechanism for modifying excitatory network interactions and the locomotor network output.

Action Potentials↗