Biomedical subjects

C J Wilson

Publications and source records attributed to C J Wilson.

At least 19 recordsLinked to original sources

PubMed2007

The lactose repressor system: paradigms for regulation, allosteric behavior and protein folding.

In 1961, Jacob and Monod proposed the operon model for gene regulation based on metabolism of lactose in Escherichia coli. This proposal was followed by an explication of allosteric behavior by Monod and colleagues. The operon model rationally depicted how genetic mechanisms can control metabolic events in response to environmental stimuli via coordinated transcription of a set of genes with related function (e.g. metabolism of lactose). The allosteric response found in the lactose repressor and many other proteins has been extended to a variety of cellular signaling pathways in all organisms. These two models have shaped our view of modern molecular biology and captivated the attention of a surprisingly broad range of scientists. More recently, the lactose repressor monomer was used as a model system for experimental and theoretical explorations of protein folding mechanisms. Thus, the lac system continues to advance our molecular understanding of genetic control and the relationship between sequence, structure and function.

Allosteric Regulation↗

PubMed2003

Five year review of the Rotaglide total knee arthroplasty.

In this study we present the outcome for patients with the Rotaglide mobile meniscal knee prosthesis implanted for osteoarthritis. All patients reviewed had this prosthesis implanted as a primary total knee Arthroplasty in Crosshouse Hospital. The minimum follow-up period was 5 years (range 5-8.2). Patients were assessed clinically by the junior author (C.W.) and results were standardised using the Hospital for Specialist Surgery (HSS) knee score. Standard radiographs were taken in antero-posterior and lateral planes to assess for loosening using the Knee Society roentgenographic system. Case notes were then examined for evidence of peri and post-operative problems. Sixty-seven patients (71 knees) were reviewed. Ninety-four percent of patients had an excellent clinical outcome with HSS scores of 85 or more. Two knees were revised, one for meniscal fracture and one for meniscal dislocation. Both of these failures were early in our series and in a total of 312 knees to date there have been no other meniscal failures. No knees were revised for aseptic loosening and there have been no deep infections. We feel this prosthesis offers a safe and effective treatment for osteoarthritis with a good clinical outcome at 5 years with a low level of complications.

Adult↗

PubMed2002

Activity patterns in a model for the subthalamopallidal network of the basal ganglia.

Based on recent experimental data, we have developed a conductance-based computational network model of the subthalamic nucleus and the external segment of the globus pallidus in the indirect pathway of the basal ganglia. Computer simulations and analysis of this model illuminate the roles of the coupling architecture of the network, and associated synaptic conductances, in modulating the activity patterns displayed by this network. Depending on the relationships of these coupling parameters, the network can support three general classes of sustained firing patterns: clustering, propagating waves, and repetitive spiking that may show little regularity or correlation. Each activity pattern can occur continuously or in discrete episodes. We characterize the mechanisms underlying these rhythms, as well as the influence of parameters on details such as spiking frequency and wave speed. These results suggest that the subthalamopallidal circuit is capable both of correlated rhythmic activity and of irregular autonomous patterns of activity that block rhythmicity. Increased striatal input to, and weakened intrapallidal inhibition within, the indirect pathway can switch the behavior of the circuit from irregular to rhythmic. This may be sufficient to explain the emergence of correlated oscillatory activity in the subthalamopallidal circuit after destruction of dopaminergic neurons in Parkinson's disease and in animal models of parkinsonism.

Action Potentials↗

PubMed2002

Utilisation of bone allograft by orthopaedic surgeons in Scotland.

The use of bone allograft in orthopaedic surgery has been predicted to increase, particularly in joint revision surgery. This has led to a potential problem with supply. Questionnaires were distributed to all 146 Consultant Orthopaedic surgeons working in Scotland in 2000. They were asked to indicate their current usage of bone and tissue allograft, any problems encountered with supply and if alternatives to allograft, such as processed bone, might be used. The questions asked were very similar to those asked in a previous study in 1995 to enable comparisons to be made. Replies were received from 125 Consultants (87%) of whom 93 reported using bone allograft. Forty-one consultants (46%) predicted an increase in their requirement for bone allograft, and 23 (26%) felt they could currently use more bone if this was available. Sixty percent of surgeons would consider using processed bone as an alternative. In comparison with figures from 1995, an increasing number of surgeons are prepared to use processed bone as an alternative to fresh frozen allograft.

Journal Article↗

PubMed2002

Corticostriatal combinatorics: the implications of corticostriatal axonal arborizations.

The complete striatal axonal arborizations of 16 juxtacellularly stained cortical pyramidal cells were analyzed. Corticostriatal neurons were located in the medial agranular or anterior cingulate cortex of rats. All axons were of the extended type and formed synaptic contacts in both the striosomal and matrix compartments as determined by counterstaining for the mu-opiate receptor. Six axonal arborizations were from collaterals of brain stem-projecting cells and the other 10 from bilaterally projecting cells with no brain stem projections. The distribution of synaptic boutons along the axons were convolved with the average dendritic tree volume of spiny projection neurons to obtain an axonal innervation volume and innervation density map for each axon. Innervation volumes varied widely, with single axons occupying between 0.4 and 14.2% of the striatum (average = 4%). The total number of boutons formed by individual axons ranged from 25 to 2,900 (average = 879). Within the innervation volume, the density of innervation was extremely sparse but inhomogeneous. The pattern of innervation resembled matrisomes, as defined by bulk labeling and functional mapping experiments, superimposed on a low background innervation. Using this sample as representative of all corticostriatal axons, the total number of corticostriatal neurons was estimated to be 17 million, about 10 times the number of striatal projection neurons.

Animals↗

PubMed2002

Regulation of the timing and pattern of action potential generation in rat subthalamic neurons in vitro by GABA-A IPSPs.

The regulation of activity in the subthalamic nucleus (STN) by GABAergic inhibition from the reciprocally connected globus pallidus (GP) plays an important role in normal movement and disorders of movement. To determine the precise manner in which GABAergic synaptic input, acting at A-type receptors, influences the firing of STN neurons, we recorded the response of STN neurons to GABA-A inhibitory postsynaptic potentials (IPSPs) that were evoked by supramaximal electrical stimulation of the internal capsule using the perforated-patch technique in slices at 37 degrees C. The mean equilibrium potential of the GABA-A IPSP (EGABA-A IPSP) was -79.4 +/- 7.0 mV. Single IPSPs disrupted the spontaneous oscillation that underlies rhythmic single-spike firing in STN neurons. As the magnitude of IPSPs increased, the effectiveness of prolonging the interspike interval was related more strongly to the phase of the oscillation at which the IPSP was evoked. Thus the largest IPSPs tended to reset the oscillatory cycle, whereas the smallest IPSPs tended to produce relatively phase-independent delays in firing. Multiple IPSPs were evoked at various frequencies and over different periods and their impact was studied on STN neurons held at different levels of polarization. Multiple IPSPs reduced and/or prevented action potential generation and/or produced sufficient hyperpolarization to activate a rebound depolarization, which generated a single spike or restored rhythmic spiking and/or generated a burst of activity. The pattern of IPSPs and the level of polarization of STN neurons were critical in determining the nature of the response. The duration of bursts varied from 20 ms to several hundred milliseconds, depending on the intrinsic rebound properties of the postsynaptic neuron. These data demonstrate that inhibitory input from the GP can produce a range of firing patterns in STN neurons, depending on the number and frequencies of IPSPs and the membrane properties and voltage of the postsynaptic neuron.

Action Potentials↗

PubMed2001

Light and electron microscopic study of corticorubral synapses in adult cat: evidence for extensive synaptic remodeling during postnatal development.

Spine-like dendritic protrusions (SLDPs) emanating from developing dendrites have been proposed to play an important role in early synaptogenesis. We previously analyzed synaptic termination sites on soma-dendritic membrane of newborn cats and found that corticorubral (CR) axons form synapses preferentially on SLDPs (Saito et al., 1997). In the present study, we examined CR synapses in adult cats to elucidate the maturation process of CR synapses in relation to SLDPs. Electron microscopic observation of serial thin sections of Phaseolus vulgaris-leucoagglutinin-labeled axons revealed that approximately 60% of CR terminals in adult cats formed synapses on dendritic spines. We also found that CR axons terminate on dendritic spines originating from the intermediate or distal dendrites of rubrospinal cells (more than 200 microm apart from the soma), in contrast to kittens in which CR fibers terminate on SLDPs originating from the proximal dendrites (less than 100 microm apart from the soma) of rubrospinal cells (Saito et al. [1997] J. Neurosci. 17:8792-8803). These results suggest that CR synapses undergo remarkable remodeling after initial termination on SLDP during postnatal development.

Aging↗

PubMed2001

Yeast artificial chromosome targeting technology: an approach for the deletion of genes in the C57BL/6 mouse.

An approach is described to modify yeast artificial chromosomes (YACs) with cassettes that can be easily excised for embryonic stem (ES) cell gene targeting experiments. YAC targeting technology (YTT) uses the WIBR/MIT-820 C57BL/6-mapped YAC library derived from the C57BL/6 mouse as the starting point for Internet- or PCR-based clone isolation, although in principle any YAC system can be used. Homologous recombination is initially performed in yeast using cassettes that function in Saccharomyces cerevisiae, Escherichia coli, and ES cells, followed by cloning or conversion of the targeted locus into a plasmid. The completed targeting vector can be transfected into C57BL/6 ES cells and clones selected with G418 followed by injection into Balb/c blastocysts. YTT increases the speed of targeting vector construction and obviates the need for extensive backcrossing to the C57BL/6 background.

Animals↗

PubMed2001

A SURF1 gene mutation presenting as isolated leukodystrophy.

Mitochondrial respiratory chain defects are increasingly recognized in patients with leukodystrophy. We report the first case of leukodystrophy with systemic cytochrome oxidase deficiency caused by a loss of function mutation in the SURF1 gene in a 2-year-old girl presenting with failure to thrive, global neurodevelopmental regression, and lactic acidosis. Although all previously reported mutations in the SURF1 gene have been found in patients with cytochrome oxidase (COX)-deficient Leigh syndrome, the phenotype associated with SURF1 protein deficiency should be extended to include leukodystrophy.

Acidosis, Lactic↗

PubMed2001

Suicidal ideation and help-negation: Not just hopelessness or prior help.

Few distressed young people seek professional psychological help and little is known about what sources of help young people seek for different problems. In suicidal youth, the process of help-negation may exacerbate poor help-seeking. Three hundred and two undergraduate university students completed a questionnaire measuring suicidal ideation, hopelessness, prior help-seeking experience, and help-seeking intentions. Participants indicated they would seek help from different sources of help for different types of problems, but friends consistently were rated as the most likely source of help. Help-negation was suggested by higher levels of suicidal ideation being associated with lower help-seeking intentions. However, the negative suicidal ideation/help-seeking-intentions relationship was not explained by hopelessness or prior help-seeking. Help-negation appears to involve more than just negative expectations regarding the future. The discussion proposes social problem-solving orientation as one of a number of potential explanatory variables.

Adult↗

PubMed2001

Plasma glutamine and ammonia concentrations in ornithine carbamoyltransferase deficiency and citrullinaemia.

A retrospective review of the plasma ammonia and glutamine concentrations during the long-term management of 7 patients with ornithine carbamoyltransferase (OCT) deficiency and three with citrullinaemia is presented. The relationship between the plasma concentrations of ammonia and glutamine is not a simple linear one and there are significant differences between the two disorders. Patients with citrullinaemia tend to have higher plasma ammonia concentrations for a given plasma glutamine concentration compared to those with OCT deficiency. The possible reasons for these differences and the implications for management are discussed.

Adolescent↗

PubMed2001

Streptococcus pneumoniae PstS production is phosphate responsive and enhanced during growth in the murine peritoneal cavity.

Differential display-PCR (DDPCR) was used to identify a Streptococcus pneumoniae gene with enhanced transcription during growth in the murine peritoneal cavity. Northern dot blot analysis and comparative densitometry confirmed a 1.8-fold increase in expression of the encoded sequence following murine peritoneal culture (MPC) versus laboratory culture or control culture (CC). Sequencing and basic local alignment search tool analysis identified the DDPCR fragment as pstS, the phosphate-binding protein of a high-affinity phosphate uptake system. PCR amplification of the complete pstS gene followed by restriction analysis and sequencing suggests a high level of conservation between strains and serotypes. Quantitative immunodot blotting using antiserum to recombinant PstS (rPstS) demonstrated an approximately twofold increase in PstS production during MPC from that during CCs, a finding consistent with the low levels of phosphate observed in the peritoneum. Moreover, immunodot blot and Northern analysis demonstrated phosphate-dependent production of PstS in six of seven strains examined. These results identify pstS expression as responsive to the MPC environment and extracellular phosphate concentrations. Presently, it remains unclear if phosphate concentrations in vivo contribute to the regulation of pstS. Finally, polyclonal antiserum to rPstS did not inhibit growth of the pneumococcus in vitro, suggesting that antibodies do not block phosphate uptake; moreover, vaccination of mice with rPstS did not protect against intraperitoneal challenge as assessed by the 50% lethal dose.

ATP-Binding Cassette Transporters↗

PubMed2001

Physiology and morphology of intratelencephalically projecting corticostriatal-type neurons in pigeons as revealed by intracellular recording and cell filling.

Much of the Wulst and dorsal ventricular ridge (DVR) in birds, which together make up the part of the avian telencephalon functionally resembling mammalian cerebral cortex, projects to the striatum. Those connections arise from neurons projecting additionally to the brainstem as well as from neurons projecting only within the telencephalon. As part of an effort to further characterize corticostriatal-type projection neurons in birds, we recorded intracellularly from neurons of the outer DVR, identified neurons projecting to the striatum by antidromic stimulation from the ipsilateral rostromedial striatum or subsequently by their axonal projection, characterized these neurons physiologically and then filled them with biocytin. As neurons in the outer DVR only project within telencephalon, neurons within it projecting to the striatum are of the intratelencephalically projecting (IT) type. Our studies suggest that: (1) the membrane potentials of avian IT-type neurons fluctuate between two preferred subthreshold values, and action potentials occur only in the 'up' state, (2) avian IT-type neurons show a time-dependent inward rectification in response to hyperpolarization and regular firing in response to constant current injection, (3) the conduction velocity of avian IT-type neurons is slow (about 0.2 m/s), (4) avian IT-type neurons possess radially disposed densely spiny dendrites but no apical dendrite, (5) avian IT-type neurons have local and distant collateral projections within the DVR, and (6) individual avian IT-type neurons give rise to an extensive terminal field within the striatum. Aside from the shape of their dendritic tree, IT-type neurons in birds closely resemble IT-type corticostriatal neurons in mammals in these various aspects, although it is presently uncertain whether this neuron type has been inherited in common by birds and mammals from stem amniotes.

Animals↗

PubMed2001

Sediment quality in Los Angeles Harbor, USA: a triad assessment.

Sediment quality in the Los Angeles and Long Beach Harbor area of southern California, USA, was assessed from 1992 to 1997 as part of the California State Water Resources Control Board's Bay Protection and Toxic Cleanup Program and the National Oceanic and Atmospheric Administration's National Status and Trends Program. The assessment strategy relied on application of various components of the sediment quality triad, combined with bioaccumulation measures, in a weight-of-evidence approach to sediment quality investigations. Results of bulk-phase chemical measurements, solid-phase amphipod toxicity tests, pore-water toxicity tests with invertebrate embryos, benthic community analyses (presented as a relative benthic index), and bioaccumulation measures indicated that inner harbor areas of this system are polluted by high concentrations of a mixture of sediment-associated contaminants and that this pollution is highly correlated with toxicity in laboratory experiments and degradation of benthic community structure. While 29% of sediment samples from this system were toxic to amphipods (Rhepoxynius abronius or Eohaustorius estuarius), 79% were toxic to abalone embryos (Haliotis rufescens) exposed to 100% pore-water concentrations. Statistical analyses indicated that amphipod survival in laboratory toxicity tests was significantly correlated with the number of crustacean species and the total number of species measured in the benthos at these stations. Triad measures were incorporated into a decision matrix designed to classify stations based on degree of sediment pollution, toxicity, benthic community degradation, and, where applicable, tissue concentrations in laboratory-exposed bivalves and feral fish.

Animals↗

PubMed2001

Statistical significance of sediment toxicity test results: threshold values derived by the detectable significance approach.

A number of methods have been employed to determine the statistical significance of sediment toxicity test results. To allow consistency among comparisons, regardless of among-replicate variability, a protocol-specific approach has been used that considers protocol performance over a large number of comparisons. Ninetieth-percentile minimum significant difference (MSD) values were calculated to determine a critical threshold for statistically significant sample toxicity. Significant toxicity threshold values (as a percentage of laboratory control values) are presented for six species and nine endpoints based on data from as many as 720 stations. These threshold values are useful for interpreting sediment toxicity data from large studies and in eliminating cases where statistical significance is assigned in individual cases because among-replicate variability is small.

Animals↗

PubMed2001

A large-scale categorization of sites in San Francisco Bay, USA, based on the sediment quality triad, toxicity identification evaluations, and gradient studies.

Sediment quality was assessed in San Francisco Bay, California, USA, using a two-tiered approach in which 111 sites were initially screened for sediment toxicity. Sites exhibiting toxicity were then resampled and analyzed for chemical contamination, recurrent toxicity, and, in some cases, benthic community impacts. Resulting data were compared with newly derived threshold values for each of the metrics in a triad-based weight-of-evidence evaluation. Sediment toxicity test results were compared with tolerance limits derived from reference site data, benthic community data were compared with threshold values for a relative benthic index based on the presence and abundance of pollution-tolerant and -sensitive taxa, and concentrations of chemicals and chemical mixtures were compared with sediment quality guideline-based thresholds. A total of 57 sites exceeded threshold values for at least one metric, and each site was categorized based on triad inferences. Nine sites were found to exhibit recurrent sediment toxicity associated with elevated contaminant concentrations, conditions that met program criteria for regulatory attention. Benthic community impacts were also observed at three of these sites, providing triad evidence of pollution-induced degradation. Multi- and univariate correlations indicated that chemical mixtures, heavy metals, chlordanes, and other organic compounds were associated with measured biological impacts in the Bay. Toxicity identification evaluations indicated that metals were responsible for pore-water toxicity to sea urchin larvae at two sites. Gradient studies indicated that the toxicity tests and benthic community metrics employed in the study predictably tracked concentrations of chemical mixtures in Bay sediments.

Animals↗

PubMed2001

Evaluation and use of sediment toxicity reference sites for statistical comparisons in regional assessments.

Sediment reference sites were used to establish toxicity standards against which to compare results from sites investigated in San Francisco Bay (California, USA) monitoring programs. The reference sites were selected on the basis of low concentrations of anthropogenic chemicals, distance from active contaminant sources, location in representative hydrographic areas of the Bay, and physical features characteristic of depositional areas (e.g., fine grain size and medium total organic carbon [TOC]). Five field-replicated sites in San Francisco Bay were evaluated over three seasons. Samples from each site were tested with nine toxicity test protocols and were analyzed for sediment grain size and concentrations of trace metals, trace organics, ammonia, hydrogen sulfide, and TOC. The candidate sites were found to have relatively low concentrations of measured chemicals and generally exhibited low toxicity. Toxicity data from the reference sites were then used to calculate numerical tolerance limits to be used as threshold values to determine which test sites had significantly higher toxicity than reference sites. Tolerance limits are presented for four standard test protocols, including solid-phase sediment tests with the amphipods Ampelisca abdita and Eohaustorius estuarius and sea urchin Strongylocentrotus purpuratus embryo/larval development tests in pore water and at the sediment-water interface (SWI). Tolerance limits delineating the lowest 10th percentile (0.10 quantile) of the reference site data distribution were 71% of the control response for Ampelisca, 70% for Eohaustorius, 94% for sea urchin embryos in pore water, and 87% for sea urchins embryos exposed at the SWI. The tolerance limits are discussed in terms of the critical values governing their calculation and the management implications arising from their use in determining elevated toxicity relative to reference conditions.

Algorithms↗

PubMed2001

An evaluation of methods for calculating mean sediment quality guideline quotients as indicators of contamination and acute toxicity to amphipods by chemical mixtures.

Mean sediment quality guideline quotients (mean SQGQs) were developed to represent the presence of chemical mixtures in sediments and are derived by normalizing a suite of chemicals to their respective numerical sediment quality guidelines (SQGs). Mean SQGQs incorporate the number of SQGs exceeded and the degree to which they are exceeded and are used for comparison with observed biological effects in the laboratory or field. The current research makes it clear, however, that the number and type of SQGs used in the derivation of these mean quotients can influence the ability of mean SQGQ values to correctly predict acute toxicity to marine amphipods in laboratory toxicity tests. To determine the optimal predictive ability of mean SQGQs, a total of 18 different chemical combinations were developed and compared. The ability of each set of mean SQGQs to correctly predict the presence and absence of acute toxicity to amphipods was determined using three independent databases (n = 605, 2753, 226). Calculated mean SQGQ values for all chemical combinations ranged from 0.002 to 100. The mean SQGQ that was most predictive of acute toxicity to amphipods is calculated as SQGQ1 = ((sigma ([cadmium]/4.21 )([copper]/270)([lead]/ 12.18)([silver]/1.77)([zinc]/ 410)([total chlordane]/6)([dieldrin]/8)([total PAHoc]/1,800)([total PCB]/400))/9). Both the incidence and magnitude of acute toxicity to amphipods increased with increasing SQGQI values. To provide better comparability between regions and national surveys, SQGQ1 is recommended to serve as the standard method for combination of chemicals and respective SQGs when calculating mean SQGQs.

Animals↗