Biomedical subjects

M J Roberts

Publications and source records attributed to M J Roberts.

At least 19 recordsLinked to original sources

PubMed2006

A novel electrode-pipette design for simultaneous recording of extracellular spikes and iontophoretic drug application in awake behaving monkeys.

We developed a novel design of an electrode-pipette combination (EPC) which allows access to brain structures in awake behaving primates without the need for guide tubes or to mechanically open the dura prior to electrode insertion. The EPC consists of an etched tungsten in glass electrode flanked by two pipettes which allow for local and highly controlled iontophoretic administration of neuroactive substances. These EPCs have excellent single cell isolation properties and are sturdy enough to penetrate the primate dura for up to 8 weeks following either a craniotomy or a dura scrape (i.e. even after substantial built up of fibrous scar tissue). We show that the EPCs can be used to selectively manipulate the cholinergic system in primate V1 during passive fixation and while animals perform an attentionally demanding task.

Acetylcholine↗

PubMed2006

Cholinergic modulation of response properties and orientation tuning of neurons in primary visual cortex of anaesthetized Marmoset monkeys.

Cortical processing is strongly influenced by the actions of neuromodulators such as acetylcholine (ACh). Early studies in anaesthetized cats argued that acetylcholine can cause a sharpening of orientation tuning functions and an improvement of the signal-to-noise ratio (SNR) of neuronal responses in primary visual cortex (V1). Recent in vitro studies have demonstrated that acetylcholine reduces the efficacy of feedback and intracortical connections via the activation of muscarinic receptors, and increases the efficacy of feed-forward connections via the activation of nicotinic receptors. If orientation tuning is mediated or enhanced by intracortical connections, high levels of acetylcholine should diminish orientation tuning. Here we investigate the effects of acetylcholine on orientation tuning and neuronal responsiveness in anaesthetized marmoset monkeys. We found that acetylcholine caused a broadening of the orientation tuning in the majority of cells, while tuning functions became sharper in only a minority of cells. Moreover, acetylcholine generally facilitated neuronal responses, but neither improved signal-to-noise ratio, nor reduced trial-to-trial firing rate variance systematically. Acetylcholine did however, reduce variability of spike occurrences within spike trains. We discuss these findings in the context of dynamic control of feed-forward and lateral/feedback connectivity by acetylcholine.

Acetylcholine↗

PubMed2004

Acetylcholine dynamically controls spatial integration in marmoset primary visual cortex.

Recent in vitro studies have shown that acetylcholine (ACh) selectively reduces the efficacy of lateral cortical connections via a muscarinic mechanism, while boosting the efficacy of thalamocortical/feed-forward connections via a nicotinic mechanism. This suggests that high levels of ACh should reduce center-surround interactions of neurons in primary visual cortex, making cells more reliant on feed-forward information. In line with this hypothesis, we show that local iontophoretic application of ACh in primate primary visual cortex reduced the extent of spatial integration, assessed by recording a neurons' length tuning. When ACh was externally applied, neurons' preferred length shifted toward shorter bars, showing reduced impact of the extra-classical receptive field. We fitted a difference and a ratio of Gaussian model to these data to determine the underlying mechanisms of this dynamic change of spatial integration. These models assume overlapping summation and suppression areas with different widths and gains to be responsible for spatial integration and size tuning. ACh significantly reduced the extent of the summation area, but had no significant effect on the extent of the suppression area. In line with previous studies, we also show that applying ACh enhanced the response in the majority of cells, especially in the later (sustained) part of the response. These findings are similar to effects of attention on neuronal activity. The natural release of ACh is strongly linked with states of arousal and attention. Our results may therefore be relevant to the neurobiological mechanism of attention.

Acetylcholine↗

PubMed2003

A new approach for assessing early osteoarthritis in the rat.

Several animal models have been developed to investigate osteoarthritis and potential disease-modifying therapeutics. However, early disease data from these models are limited by the resolution of current imaging modalities. In this in-vitro study, an optical coherence tomography (OCT) system with an axial resolution of 15 micro m was used to track sequential changes in osteoarthritic rat knees. Osteoarthritis was induced via transection of the medial collateral ligament and an artificial full thickness meniscal tear. Imaging occurred at one, two, and three weeks after surgery. OCT successfully detected early signs of osteoarthritic change, including alteration of the cartilage surface and disruption of the bone-cartilage interface. This study demonstrates that OCT, along with the induction of mechanical injury, provides an excellent model for monitoring the sequential changes of osteoarthritis.

Animals↗

PubMed2003

New technology for assessing microstructural components of tendons and ligaments.

This study investigated the ability of optical coherence tomography (OCT), a recently developed technology with micron-scale resolution, to assess the microstructure of tendons and ligaments. In vitro structural- and polarization-sensitive OCT was performed on human ACL, Achilles tendon, and biceps tendon (obtained postmortem). Histology was performed on all imaged samples and compared to the corresponding OCT data. OCT images correlated well with histology. Most importantly, through polarization-sensitive OCT, the collagen in normal tissue was easily distinguished from the surrounding, supportive tissue due to the birefringent properties of organized collagen. Since the integrity of collagen is an important indicator of structural stability and pathologic state, the ability of OCT to assess collagen could be a powerful diagnostic tool in assessing tendon and ligament properties.

Humans↗

PubMed2003

The experience of the intensive care unit in a British Army field hospital during the 2003 Gulf conflict.

Over the last few years the Surgeon General's Department has overseen a major update in equipment scales for medical units in the field; anaesthesia and intensive care. This is to meet the aspiration of the Defence Chiefs, that injured servicemen on active service should receive the same standard of care as available in the United Kingdom. This paper discusses the experiences of the Intensive Care Unit operating within a Field Hospital both during the initial war fighting phase and subsequent peace keeping phase of the 2003 Gulf conflict (OP TELIC). Observations are made on patient activity, treatment strategy, and equipment adequacy.

Female↗

PubMed2002

Chemistry for peptide and protein PEGylation.

Poly(ethylene glycol) (PEG) is a highly investigated polymer for the covalent modification of biological macromolecules and surfaces for many pharmaceutical and biotechnical applications. In the modification of biological macromolecules, peptides and proteins are of extreme importance. Reasons for PEGylation (i.e. the covalent attachment of PEG) of peptides and proteins are numerous and include shielding of antigenic and immunogenic epitopes, shielding receptor-mediated uptake by the reticuloendothelial system (RES), and preventing recognition and degradation by proteolytic enzymes. PEG conjugation also increases the apparent size of the polypeptide, thus reducing the renal filtration and altering biodistribution. An important aspect of PEGylation is the incorporation of various PEG functional groups that are used to attach the PEG to the peptide or protein. In this paper, we review PEG chemistry and methods of preparation with a particular focus on new (second-generation) PEG derivatives, reversible conjugation and PEG structures.

Drug Carriers↗

PubMed2001

Optimizing the energy status of skin cells during solar radiation.

Ionizing- and ultraviolet-radiation cause cell damage or death by directly altering DNA and protein structures and by production of reactive oxygen species (ROS) and reactive carbonyl species (RCS). These processes disrupt cellular energy metabolism at multiple levels. The formation of DNA strand breaks activates signaling pathways that consume NAD, which can lead to the depletion of cellular ATP. Poly(ADP)-ribose polymerase (PARP-1) is the enzyme responsible for much of the NAD degradation following DNA damage, although numerous other PARPs have been discovered recently that await functional characterization. Studies on mouse epidermis in vivo and on human cells in culture have shown that UV-B radiation provokes the transient degradation of NAD and the synthesis of ADP-ribose polymers by PARP-1. This enzyme functions as a component of a DNA damage surveillance network in eukaryotic cells to determine the fate of cells following genotoxic stress. Additionally, the activation of PARP-1 results in the activation of a nuclear proteasome that degrades damaged nuclear proteins including histones. Identifying approaches to optimize these responses while maintaining the energy status of cells is likely to be very important in minimizing the deleterious effects of solar radiation on skin.

Animals↗

PubMed2001

Task-switching costs, Stroop-costs, and executive control: a correlational study.

Three correlational studies investigated the relationship between the time costs associated with Stroop stimuli (Stroop-costs) with the time costs associated with task-switching (switch-costs) obtained from colour-word stimuli and digit stimuli. In all studies, large and significant positive correlations were found between different measures of switch-costs. However, only small (and sometimes non-significant) correlations were obtained between the different measures of Stroop-costs and between measures of Stroop-costs and measures of switch-costs. The results are taken as evidence for the existence of some common or shared specialized mechanisms involved in task-switching, which are different from those used to overcome Stroop interference.

Adolescent↗

PubMed2001

Inspection times, the change task, and the rapid-response selection task.

Three experiments are reported, which are based upon the Wason four-card selection task inspection time paradigm, in which subjects solve computer-presented trials while using a mouse to indicate the card currently under consideration. Evans (1996) had shown that selected cards were inspected for longer than non-selected cards, and this was taken as support for the existence of pre-conscious heuristic processes that direct attention towards relevant aspects of a problem. However, Roberts (1998b) suggested that this inspection time effect is artefactual, due to task format induced biases. Experiment 1 utilized a "change" task: Cards were presented either as selected or not selected, and subjects changed these where necessary. This demonstrated an association between card selection and inspection time independently of one between the act of response and inspection time. Experiment 2 utilized a standard selection task, but subjects either responded within 2 s of each card presentation, or made selections with no time pressure. The curtailment of thinking time increased matching behaviour--more cards matching the terms in the rules were selected--and was replicated in Experiment 3 using a within-subjects design. Overall, the data support Evans' heuristic-analytic framework albeit with some caveats.

Adolescent↗

PubMed2001

Pharmacodynamic and pharmacokinetic characterization of poly(ethylene glycol) conjugation to met-enkephalin analog [D-Pen2, D-Pen5]-enkephalin (DPDPE).

Poly(ethylene glycol), or PEG, conjugation to proteins and peptides is a growing technology used to enhance efficacy of therapeutics. This investigation assesses pharmacodynamic and pharmacokinetic characteristics of PEG-conjugated [D-Pen2,D-Pen5]-enkephalin (DPDPE), a met-enkephalin analog, in rodent (in vivo, in situ) and bovine (in vitro) systems. PEG-DPDPE showed increased analgesia (i.v.) compared with nonconjugated form (p < 0.01), despite a 172-fold lower binding affinity for the delta-opioid receptor. [125I]PEG-DPDPE had a 36-fold greater hydrophilicity (p < 0.01) and 12% increase in the unbound plasma protein fraction (p < 0.01), compared with [(125)I]DPDPE. [125I]PEG-DPDPE had a 2.5-fold increase in elimination half-life (p < 0.01), 2.7-fold decrease in volume of distribution (p < 0.01), and a 7-fold decrease in plasma clearance rate (p < 0.01) to [125I]DPDPE. Time course distribution showed significant concentration differences (p < 0.01) in plasma, whole blood, liver, gallbladder, gastrointestinal (GI) content, GI tract, kidneys, spleen, urine, and brain (brain, p < 0.05), between the conjugated and nonconjugated forms. Increased brain uptake of [(125)I]PEG-DPDPE corresponded to analgesia data. [125I]PEG-DPDPE in brain was shown to be 58.9% intact, with 41.1% existing as [125I]DPDPE (metabolite), whereas [125I]DPDPE was 25.7% intact in the brain (at 30 min). In vitro P-glycoprotein affinity was shown for [125I]DPDPE (p < 0.01) but not shown for [125I]PEG-DPDPE. In vitro saturable uptake, with 100 microM DPDPE, was shown for [125I]PEG-DPDPE (p < 0.05). In this study, PEG-conjugated DPDPE seems to act as a prodrug, enhancing peripheral pharmacokinetics, while undergoing hydrolysis in the brain and allowing nonconjugated DPDPE to act at the receptor.

Analgesics, Opioid↗

PubMed2000

An experimental study of strategy development.

Three experiments are reported in which the strategy usage for a compass point directions task was investigated. For this task, people may use either an efficient cancellation strategy or an inefficient spatial strategy (see Roberts, Gilmore, & Wood, 1997). Experiment 1, together with Experiment 2, showed that users of cancellation are unlikely to have explicit prior knowledge of this strategy; instead they discover it as a result of experience with the task. Experiment 1 also showed that strategy selection is unlikely to be based on stylistic preferences, and that reducing the cognitive demands of the task does not increase the discovery of cancellation. Experiment 3 showed that evaluation of strategy validity is also of importance: Unsuccessful evaluation may prevent the selection of a newly discovered strategy, even if it is the more efficient method.

Adult↗

PubMed1999

Photoimmobilization of organophosphorus hydrolase within a PEG-based hydrogel.

Organophosphorous hydrolase (OPH) was physically and covalently immobilized within photosensitive polyethylene glycol (PEG)-based hydrogels. The hydroxyl ends of branched polyethylene glycol (b-PEG, four arms, MW = 20,000) were modified with cinnamylidene acetate groups to give water-soluble, photosensitive PEG macromers (b-PEG-CA). The b-PEG-CA macromers underwent photocrosslinking reaction and formed gels upon UV irradiation (>300 nm) in the presence of erythrosin B. Native OPH was pegylated with cinnamylidene-terminated PEG chains (MW = 3400) to be covalently linked with the b-PEG-CA macromers during photogelation. The effect of pegylation on the stability of the enzyme was determined. Furthermore, the effect of enzyme concentration, wavelength of irradiation, and photosensitizer on the stability of the entrapped enzyme was also investigated. The pegylated OPH was more stable than the native enzyme, and the OPH-containing gels exhibited superior stability than the soluble enzyme preparations.

Aryldialkylphosphatase↗

PubMed1999

The CompPAC and PortaPAC portable ventilators bench tests and field experience.

The military and some civilian rescue agencies have a requirement for portable ventilators in the anaesthetic, resuscitation and pre-hospital environment. This paper describes two new portable ventilators specifically designed to satisfy the military requirement for lightweight, robust and versatile equipment which can also be used in a contaminated environment.

Adult↗

PubMed1998

Use of administrative personnel in hospitals: a three nation comparison.

Differences in the costs of health care systems among industrialized countries has been the focus of several studies. Labor costs, specifically the amount of resources used for administration, are considered to contribute to differences in overall health care costs. To determine differences in the use of labor resources, especially administrative and managerial, among American, Austrian and German hospitals, we use a convenience sample of one Austrian, one German and two United States (US) tertiary care centers. In our analysis we used payroll data of the four hospitals. First, we categorized job titles and created job categories. Subsequently, we calculated full time equivalents (FTEs) per job category and compared them across countries. Adjustments were made for differences in health systems. The main outcome measures were FTEs per patient day and per discharge in each job category. In the US hospitals > 19% of FTEs were in administrative categories as compared with < 8% in the European hospitals. For administrative managers, US hospitals used > 11 times the labor per patient day of the European institutions. Among administrative areas, the largest absolute FTE difference was in financial operations. US hospitals used > 5 FTEs of personnel per 10,000 patient days versus < 1.0 FTE in the European hospitals. Given the kinds of administrative work done in US hospitals compared to Austria and Germany, differences in the organization and financing of these countries' health care systems may account for an important part of the higher number of US personnel.

Austria↗

PubMed1998

Attachment of degradable poly(ethylene glycol) to proteins has the potential to increase therapeutic efficacy.

Capillary electrophoresis (CE) was investigated for characterizing poly(ethylene glycol) (PEG) attachment ("PEGylation") and PEG removal ("dePEGylation") of proteins. Lysozyme was used as a model protein because it is one of the best understood enzymes, has a high ionic strength (high pI value; thus making it suitable for CE), and has a tertiary structure that is known with high resolution. Several PEG derivatives, both hydrolytically degradable and nondegradable and with varying reactivities toward amino groups, were used to couple to amino groups (six epsilon-amino and one alpha-amino) on the surface of the protein. Capillary electrophoresis was found to be useful in following both the PEGylation and dePEGylation of lysozyme. Capillary electrophoresis separation is based on the size of the conjugate, which is determined by the number and molecular weight of the PEG that is attached. Baseline resolution was obtained between the peaks for each PEG chain attached per protein molecule ("PEGmers") for PEG molecular weights >5000, although individual PEGmers could be recognized at lower molecular weights without baseline separation. Highly modified lysozyme showed complete inactivation, but when released from the degradable PEG, regained >60% of the original in vitro activity. The sites of PEGylation were determined using a tryptic map of the modified and unmodified protein. Typically, peptide fragments are separated by reversed-phase HPLC, but we show that CE can provide a complementary separation technique for determining sites of PEGylation. Capillary electrophoresis has advantages of high efficiency separations, rapid analysis, and ease of use.

Drug Carriers↗

PubMed1998

Reductive amination using poly(ethylene glycol) acetaldehyde hydrate generated in situ: applications to chitosan and lysozyme.

Covalent linkage of poly(ethylene glycol) (PEG) to drug molecules results in water-soluble conjugates with altered bioavailability, pharmacokinetics, immunogenic properties, and biological activities. For drugs bearing one or more amino groups, reductive amination is a potentially useful method for conjugation to PEG. PEG acetaldehyde has been used for this purpose, but its ease of polymerization under certain conditions and its susceptibility to air oxidation have caused some problems in its application. A simple and reliable method for preparation and use in reductive amination of PEG acetaldehyde hydrate generated in situ by hydrolysis of PEG acetaldehyde diethylacetal is demonstrated. PEG acetaldehyde diethylacetal is prepared in high yield and purity by reaction of PEG with chlorodiethylacetal in dioxane in the presence of finely powdered sodium hydroxide under heterogeneous conditions. PEG acetaldehyde hydrate is generated in solution by hydrolysis in aqueous acids. Solutions of the hydrate may be used directly, in conjunction with sodium cyanoborohydride, to effect reductive amination. We demonstrate application of these methods in PEGylation of lysozyme and chitosan to form water-soluble methoxy poly(ethylene glycol) (mPEG) derivatives and PEG-chitosan hydrogels.

Benzoates↗

PubMed1998

Distribution and excretion of sertraline and N-desmethylsertraline in human milk.

AIMS: To characterise milk/plasma (M/P) ratio and infant exposure, for sertraline and N-desmethylsertraline, in breast-feeding women taking sertraline for the treatment of depression. METHODS: Eight women (mean age 28 years) taking sertraline (1.05 mg kg(-1) day(-1)) and their infants (mean age 5.7 months) were studied. Sertraline and N-desmethylsertraline in plasma and milk were measured by high-performance liquid chromatography over a 24 h dose interval at steady-state. M/P values were estimated from area under the plasma and milk concentration-time curves. All milk produced was collected over the dose interval. Infant exposure was estimated as the product of actual or estimated milk production, and average drug concentration in milk, normalized to body weight and expressed as a percentage of the weight-adjusted maternal dose. RESULTS: Mean milk production was 321 ml day(-1) (range 34-974 ml). Mean M/P values of 1.93 and 1.64 were calculated for sertraline and N-desmethylsertraline respectively. Infant exposure estimated from actual milk produced was 0.2% and 0.3% of the weight-adjusted maternal dose for sertraline and N-desmethylsertraline (as sertraline equivalents) respectively. When calculated from estimated milk production (0.15 l kg(-1) day(-1)), infant exposure was significantly greater (P<0.0001) at 0.90% and 1.32% for sertraline and N-desmethylsertraline respectively. Neither sertraline nor its N-desmethyl metabolite could be detected in plasma samples from the four infants tested. No adverse effects were observed in any of the eight infants and all had achieved normal developmental milestones. CONCLUSIONS: Irrespective of the method of calculation of infant exposure, the mean total dose of sertraline and its N-desmethyl metabolite transmitted to infants via breast-feeding is low and unlikely to cause any significant adverse effects.

1-Naphthylamine↗