Biomedical subjects

Michael O'Shea

Publications and source records attributed to Michael O'Shea.

At least 19 recordsLinked to original sources

PubMed2007

Escape flight initiation in the fly.

Visually evoked escape flight initiation in Drosophila, according to the accepted account, involves a rapid extension of the middle legs that propels the fly into the air while the wings are still folded. This description has remained unchallenged and is accounted for in terms of the activation of a simple neural circuit, the Giant fibre (GF) system. The accepted description of escape is however inconsistent with the sequence of events recorded when the GF system is stimulated. Specifically, previous electrophysiological recordings have shown that the wing depressor muscles are activated before the wings are in a position to be depressed because they have not yet been elevated. Here we show that the accepted behavioural description is wrong. Escape flight initiation actually begins with wing elevation. The current model of the GF system is revised to account for the actual sequence of events that occur when a fly escapes.

Animals↗

PubMed2006

Modulation of serotonergic neurotransmission by nitric oxide.

Nitric oxide (NO) and serotonin (5-HT) are two neurotransmitters with important roles in neuromodulation and synaptic plasticity. There is substantial evidence for a morphological and functional overlap between these two neurotransmitter systems, in particular the modulation of 5-HT function by NO. Here we demonstrate for the first time the modulation of an identified serotonergic synapse by NO using the synapse between the cerebral giant cell (CGC) and the B4 neuron within the feeding network of the pond snail Lymnaea stagnalis as a model system. Simultaneous electrophysiological recordings from the pre- and postsynaptic neurons show that blocking endogenous NO production in the intact nervous system significantly reduces the B4 response to CGC activity. The blocking effect is frequency dependent and is strongest at low CGC frequencies. Conversely, bath application of the NO donor DEA/NONOate significantly enhances the CGC-B4 synapse. The modulation of the CGC-B4 synapse is mediated by the soluble guanylate cyclase (sGC)/cGMP pathway as demonstrated by the effects of the sGC antagonist 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (ODQ). NO modulation of the CGC-B4 synapse can be mimicked in cell culture, where application of 5-HT puffs to isolated B4 neurons simulates synaptic 5-HT release. Bath application of diethylamine NONOate (DEA/NONOate) enhances the 5-HT induced response in the isolated B4 neuron. However, the cell culture experiment provided no evidence for endogenous NO production in either the CGC or B4 neuron suggesting that NO is produced by an alternative source. Thus we conclude that NO modulates the serotonergic CGC-B4 synapse by enhancing the postsynaptic 5-HT response.

Animals↗

PubMed2006

Role of delayed nonsynaptic neuronal plasticity in long-term associative memory.

BACKGROUND: It is now well established that persistent nonsynaptic neuronal plasticity occurs after learning and, like synaptic plasticity, it can be the substrate for long-term memory. What still remains unclear, though, is how nonsynaptic plasticity contributes to the altered neural network properties on which memory depends. Understanding how nonsynaptic plasticity is translated into modified network and behavioral output therefore represents an important objective of current learning and memory research. RESULTS: By using behavioral single-trial classical conditioning together with electrophysiological analysis and calcium imaging, we have explored the cellular mechanisms by which experience-induced nonsynaptic electrical changes in a neuronal soma remote from the synaptic region are translated into synaptic and circuit level effects. We show that after single-trial food-reward conditioning in the snail Lymnaea stagnalis, identified modulatory neurons that are extrinsic to the feeding network become persistently depolarized between 16 and 24 hr after training. This is delayed with respect to early memory formation but concomitant with the establishment and duration of long-term memory. The persistent nonsynaptic change is extrinsic to and maintained independently of synaptic effects occurring within the network directly responsible for the generation of feeding. Artificial membrane potential manipulation and calcium-imaging experiments suggest a novel mechanism whereby the somal depolarization of an extrinsic neuron recruits command-like intrinsic neurons of the circuit underlying the learned behavior. CONCLUSIONS: We show that nonsynaptic plasticity in an extrinsic modulatory neuron encodes information that enables the expression of long-term associative memory, and we describe how this information can be translated into modified network and behavioral output.

Animals↗

PubMed2006

Associative memory stored by functional novel pathway rather than modifications of preexisting neuronal pathways.

Associative conditioning involves changes in the processing pathways activated by sensory information to link the conditioned stimulus (CS) to the conditioned behavior. Thus, conditioning can recruit neuronal elements to form new pathways for the processing of the CS and/or can change the strength of existing pathways. Using a behavioral and systems level electrophysiological approach on a tractable invertebrate circuit generating feeding in the mollusk Lymnaea stagnalis, we identified three independent pathways for the processing of the CS amyl acetate used in appetitive conditioning. Two of these pathways, one suppressing and the other stimulating feeding, mediate responses to the CS in naive animals. The effects of these two pathways on feeding behavior are unaltered by conditioning. In contrast, the CS response of a third stimulatory pathway is significantly enhanced after conditioning, becoming an important contributor to the overall CS response. This is unusual because, in most of the previous examples in which naive animals already respond to the CS, memory formation results from changes in the strength of pathways that mediate the existing response. Here, we show that, in the molluscan feeding system, both modified and unmodified pathways are activated in parallel by the CS after conditioning, and it is their integration that results in the conditioned response.

Animals↗

PubMed2005

The role of neonatal networks.

A neonatal network is a collaboration involving more than one clinical site where a common protocol is used for a randomized trial, observational study, or quality improvement project. Because the prevalence of important outcomes (e.g., death or neurodevelopmental impairment) is low among neonates, multi-site studies have been an essential contributor to the identification of interventions for improving the health of neonates. In this review we summarize key aspects of the conduct of multi-site studies and describe some of the prominent accomplishments and contributions of neonatal networks. Important contributions of randomized trials and observational studies include the identification, and assessment, of potential strategies for prevention of cerebral palsy, chronic lung disease, and blindness due to retinopathy of prematurity. In addition, quality improvement projects by neonatal networks have greatly facilitated the dissemination of information about, and implementation of, evidence-based interventions.

Biomedical Research↗

PubMed2005

Activation of MAPK is necessary for long-term memory consolidation following food-reward conditioning.

Although an important role for the mitogen-activated protein kinase (MAPK) has been established for memory consolidation in a variety of learning paradigms, it is not known if this pathway is also involved in appetitive classical conditioning. We address this question by using a single-trial food-reward conditioning paradigm in the freshwater snail Lymnaea stagnalis. This learning paradigm induces protein synthesis-dependent long-term memory formation. Inhibition of MAPK phosphorylation blocked long-term memory consolidation without affecting the sensory and motor abilities of the snails. Thirty minutes after conditioning, levels of MAPK phosphorylation were increased in extracts from the buccal and cerebral ganglia. These ganglia are involved in the generation, modulation, and plasticity of the feeding behavior. We also detected an increase in levels of MAPK phosphorylation in the peripheral tissue around the mouth of the snails where chemoreceptors are located. Although an increase in MAPK phosphorylation was shown to be essential for food-reward conditioning, it was also detected in snails that were exposed to the conditioned stimulus (CS) or the unconditioned stimulus (US) alone, suggesting that phosphorylation of MAPK is necessary but not sufficient for learning to occur.

Animals↗

PubMed2005

Modeling cooperative volume signaling in a plexus of nitric-oxide-synthase-expressing neurons.

In vertebrate and invertebrate brains, nitric oxide (NO) synthase (NOS) is frequently expressed in extensive meshworks (plexuses) of exceedingly fine fibers. In this paper, we investigate the functional implications of this morphology by modeling NO diffusion in fiber systems of varying fineness and dispersal. Because size severely limits the signaling ability of an NO-producing fiber, the predominance of fine fibers seems paradoxical. Our modeling reveals, however, that cooperation between many fibers of low individual efficacy can generate an extensive and strong volume signal. Importantly, the signal produced by such a system of cooperating dispersed fibers is significantly more homogeneous in both space and time than that produced by fewer larger sources. Signals generated by plexuses of fine fibers are also better centered on the active region and less dependent on their particular branching morphology. We conclude that an ultrafine plexus is configured to target a volume of the brain with a homogeneous volume signal. Moreover, by translating only persistent regional activity into an effective NO volume signal, dispersed sources integrate neural activity over both space and time. In the mammalian cerebral cortex, for example, the NOS plexus would preferentially translate persistent regional increases in neural activity into a signal that targets blood vessels residing in the same region of the cortex, resulting in an increased regional blood flow. We propose that the fineness-dependent properties of volume signals may in part account for the presence of similar NOS plexus morphologies in distantly related animals.

Algorithms↗

PubMed2005

Timed and targeted differential regulation of nitric oxide synthase (NOS) and anti-NOS genes by reward conditioning leading to long-term memory formation.

In a number of neuronal models of learning, signaling by the neurotransmitter nitric oxide (NO), synthesized by the enzyme neuronal NO synthase (nNOS), is essential for the formation of long-term memory (LTM). Using the molluscan model system Lymnaea, we investigate here whether LTM formation is associated with specific changes in the activity of members of the NOS gene family: Lym-nNOS1, Lym-nNOS2, and the antisense RNA-producing pseudogene (anti-NOS). We show that expression of the Lym-nNOS1 gene is transiently upregulated in cerebral ganglia after conditioning. The activation of the gene is precisely timed and occurs at the end of a critical period during which NO is required for memory consolidation. Moreover, we demonstrate that this induction of the Lym-nNOS1 gene is targeted to an identified modulatory neuron called the cerebral giant cell (CGC). This neuron gates the conditioned feeding response and is an essential part of the neural network involved in LTM formation. We also show that the expression of the anti-NOS gene, which functions as a negative regulator of nNOS expression, is downregulated in the CGC by training at 4 h after conditioning, during the critical period of NO requirement. This appears to be the first report of the timed and targeted differential regulation of the activity of a group of related genes involved in the production of a neurotransmitter that is necessary for learning, measured in an identified neuron of known function. We also provide the first example of the behavioral regulation of a pseudogene.

Animals↗

PubMed2005

Risk factors for nosocomial infections in selected neonatal intensive care units in Colombia, South America.

OBJECTIVE: This study was designed to identify risk factors for nosocomial infections among infants admitted into eight neonatal intensive care units in Colombia. Knowledge of modifiable risk factors could be used to guide the design of interventions to prevent the problem. STUDY DESIGN: Data were collected prospectively from eight neonatal units. Nosocomial infection was defined as culture-proven infection diagnosed after 72 hours of hospitalization, resulting in treatment with antibiotics for >3 days. Associations were expressed as odds ratios. Logistic regression was used to adjust for potential confounders. RESULTS: From a total of 1504 eligible infants, 80 were treated for 127 episodes of nosocomial infection. Logistic regression analysis identified the combined exposure to postnatal steroids and H2-blockers, and use of oral gastric tubes for enteral nutrition as risk factors significantly associated with nosocomial infection. CONCLUSION: Nosocomial infections in Colombian neonatal intensive care units were associated with modifiable risk factors including use of postnatal steroids and H2-blockers.

Colombia↗

PubMed2005

Video and CD-ROM as a training tool for performing neurologic examinations of 1-year-old children in a multicenter epidemiologic study.

In lieu of traditional training of examiners to identify cerebral palsy on a neurologic examination at age 1 year, we proposed an alternative approach using a multimedia training video and CD-ROM we developed after a two-step validation process. We hypothesized that use of CD-ROM interactive training will lead to reliable and valid performance of the neurologic examination by both pediatric neurologists and nonpediatric neurologists. All examiners were asked to take one of six interobserver variability tests found on the CD-ROM on two occasions. In the first interobserver variability evaluation, 89% (531 of 594) of the responses agreed with the gold standard responses. Following annotated feedback to the examiners about the two items that had a 60% correct rate, the correct response rate rose to 93% (114 of 123). In the second interobserver variability evaluation, 88% (493 of 560) of the responses agreed with the gold standard responses. Following annotated feedback to the examiners about the four items that had a 70% correct rate, the correct response rate rose to 96% (104 of 108). Interactive CD-ROM examination training is an efficient and cost-effective means of training both neurologists and non-neurologists to perform structured neurologic examinations in 1-year-old children. It provides an effective means to evaluate interobserver variability, offers a route for feedback, and creates an opportunity to reevaluate variability, both immediately and at periodic intervals.

CD-ROM↗

PubMed2005

Natural antisense RNAs in the nervous system.

Natural antisense RNAs are endogenous molecules that are complementary to RNA transcripts of already established function. They were discovered first in prokaryotes in which they are now recognised as an important component of molecular mechanisms involved in the regulation of gene expression. Recently, through the cumulative efforts of molecular biologists and bioinformaticians, natural antisense RNAs have been demonstrated in significant numbers in eukaryotic systems also. Probably the most exciting outcome of these studies is that natural antisense RNAs are particularly prevalent in the nervous system. Here we discuss the major known types of natural antisense RNAs in eukaryotic systems and focus on their potential roles in the regulation of gene expression in the brain.

Animals↗

PubMed2004

Central localization of plasticity involved in appetitive conditioning in Lymnaea.

Learning to associate a conditioned (CS) and unconditioned stimulus (US) results in changes in the processing of CS information. Here, we address directly the question whether chemical appetitive conditioning of Lymnaea feeding behavior involves changes in the peripheral and/or central processing of the CS by using extracellular recording techniques to monitor neuronal activity at two stages of the sensory processing pathway. Our data show that appetitive conditioning does not affect significantly the overall CS response of afferent nerves connecting chemosensory structures in the lips and tentacles to the central nervous system (CNS). In contrast, neuronal output from the cerebral ganglia, which represent the first central processing stage for chemosensory information, is enhanced significantly in response to the CS after appetitive conditioning. This demonstrates that chemical appetitive conditioning in Lymnaea affects the central, but not the peripheral processing of chemosensory information. It also identifies the cerebral ganglia of Lymnaea as an important site for neuronal plasticity and forms the basis for detailed cellular studies of neuronal plasticity.

Animals↗

PubMed2004

Cumulative radiation dose caused by radiologic studies in critically ill trauma patients.

BACKGROUND: Critically ill trauma patients undergo many radiologic studies, but the cumulative radiation dose is unknown. The purpose of this study was to estimate the cumulative effective dose (CED) of radiation resulting from radiologic studies in critically ill trauma patients. METHODS: The study group was composed of trauma patients at an urban Level I trauma center with surgical intensive care unit length of stay (LOS) greater than 30 days. The radiology records were reviewed. A typical effective dose per study for each type of plain film radiograph, computed tomographic scan, fluoroscopic study, and nuclear medicine study was used to calculate CED. RESULTS: Forty-six patients met criteria. The mean surgical intensive care unit and hospital LOS were 42.7 +/- 14.0 and 59.5 +/- 28.5 days, respectively. The mean Injury Severity Score was 32.2 +/- 15.0. The mean number of studies per patient was 70.1 +/- 29.0 plain film radiographs, 7.8 +/- 4.1 computed tomographic scans, 2.5 +/- 2.6 fluoroscopic studies, and 0.065 +/- 0.33 nuclear medicine study. The mean CED was 106 +/- 59 mSv per patient (range, 11-289 mSv; median, 104 mSv). Among age, mechanism, Injury Severity Score, and LOS, there was no statistically significant predictor of high CED. The mean CED in the study group was 30 times higher than the average yearly radiation dose from all sources for individuals in the United States. The theoretical additional morbidity attributable to radiologic studies was 0.78%. CONCLUSION: From a radiobiologic perspective, risk-to-benefit ratios of radiologic studies are favorable, given the importance of medical information obtained. Current practice patterns regarding use of radiologic studies appear to be acceptable.

Accidents, Traffic↗

PubMed2004

Randomized trial of a pain control infusion pump following inguinal hernia repair.

BACKGROUND: Continuous ambulatory analgesia following various surgical procedures is gaining popularity. The purpose of the present paper is to evaluate this form of analgesia following open anterior inguinal hernia repair by way of a pain control infusion pump (PCIP). METHODS: Forty-eight consecutive patients scheduled for inguinal hernia repair were enrolled in a double-blind, randomized, placebo-controlled trial. Following the repair, a catheter was placed in the wound connected to an external PCIP, delivering either ropivacaine or normal saline at a fixed rate of 4 mL/ h. Regular 4-hourly postoperative pain observations according to a Visual Analogue Score (VAS) and any rescue opioid requirements were recorded, at different levels of mobility. RESULTS: Data analysis included 23 (ropivacaine) and 24 (saline) patients in each group, with one exclusion. There were no adverse effects of the PCIP in either group. Patients in the ropivacaine group ('active pump') had lower mean pain scores and less rescue analgesia compared to the saline group ('placebo pump'). This clinical effect was found to be more striking at increased levels of mobility. Importantly, no patients in the ropivacaine group required any rescue analgesia after the first 4-h block postoperatively. CONCLUSION: The PCIP provided safe and adequate analgesia following inguinal hernia repair. It provided effective analgesia especially when patients were mobilizing. This has implications for earlier discharge from hospital and associated cost-savings.

Analgesia, Patient-Controlled↗

PubMed2003

Longitudinal multicenter follow-up of high-risk infants: why, who, when, and what to assess.

This article reviews experience with longitudinal follow-up of high-risk infants in the National Institute of Child Health and Human Development (NICHD) Neonatal Research Network. In 1993, the Network initiated a research protocol to provide longitudinal follow-up of infants with birth weight less than 1001 g and infants with higher birth weights who participated in certain Network randomized trials. Infants are assessed at 18 to 22 months corrected age (corrected for degree of prematurity) using measures of the infant's health, growth, neuromotor, and early cognitive functioning, language, behavior, and family resources. Data from these assessments have been used to investigate potentially modifiable risk factors for cerebral palsy and delayed early cognitive functioning and to evaluate the risks and benefits of interventions assessed in randomized trials. The Network's experience thus far suggests that longitudinal follow-up can provide valuable information about treatments given to fetuses and neonates.

Cerebral Palsy↗

PubMed2003

Outcome and complications of intraoperative hemodialysis during cardiopulmonary bypass with potassium-rich cardioplegia.

BACKGROUND: Potassium-rich cardioplegia has advantages over other cardioplegic solutions in preserving the myocardium during cardiopulmonary bypass, but it is avoided in patients with renal failure because of hyperkalemia. METHODS: We first determined the ability of intraoperative hemodialysis (IHD) to remove potassium during cardiopulmonary bypass with potassium-rich cardioplegia in 9 patients by measuring potassium levels in all dialysate and urine. We then studied 24 patients with renal failure, grouped with the 9 previous patients, to assess safety, rebound hyperkalemia, and patient outcome with this technique. RESULTS: In the first phase, 9 patients were administered 128 +/- 11 mmol of potassium in potassium-rich cardioplegia, and IHD removed 157 +/- 23 mmol. Urinary potassium excretion was only 10 +/- 3 mmol. Potassium removal occurred at a rate of 1.25 mmol/min with 0-mEq/L (mmol/L) potassium dialysate and a rate of 0.75 mmol/min with 3.0-mEq/L (mmol/L) potassium dialysate. In all 33 patients, successful initiation of cardiac rhythm occurred after cardiopulmonary bypass, and 5 patients had cardiac arrhythmias possibly from hypokalemia. In the next 24 hours, 5 dialysis-dependent patients developed hyperkalemia (potassium > 5.2 mEq/L [mmol/L]) requiring hemodialysis. Postoperative hemodialysis was delayed 2 to 3 days in the other patients. The overall death rate was 24% at 30 days. CONCLUSION: IHD effectively and safely removes potassium administered during potassium-rich cardioplegia during cardiopulmonary bypass in patients with renal failure and prevents postoperative hyperkalemia in the majority of patients. Overall mortality in patients with acute and chronic renal failure undergoing cardiac surgery is high irrespective of control of potassium balance in these patients.

Aged↗

PubMed2003

Local evolvability of statistically neutral GasNet robot controllers.

In this paper we introduce and apply the concept of local evolvability to investigate the behaviour of populations during evolutionary search. We focus on the evolution of GasNet neural network controllers for a robotic visual discrimination problem, showing that the evolutionary process undergoes long neutral fitness epochs. We show that the local evolvability properties of the search space surrounding a group of statistically neutral solutions do vary across the course of an evolutionary run, especially during periods of population takeover. However, once takeover is complete there is no evidence for further increase in local evolvability across fitness epochs. We also see no evidence for the neutral evolution of increased solution robustness, but show that this may be due to the ability of evolutionary algorithms to focus search on volumes of the fitness landscape with above average robustness.

Adaptation, Physiological↗

PubMed2003

Cyclic AMP response element-binding (CREB)-like proteins in a molluscan brain: cellular localization and learning-induced phosphorylation.

The phosphorylation and the binding to DNA of the nuclear transcription factor, cyclic adenosine 3',5'-monophosphate (cAMP) response element-binding protein (CREB) are conserved key steps in the molecular cascade leading to the formation of long-term memory (LTM). Here, we characterize, for the first time, a CREB1-like protein in the central nervous system (CNS) of Lymnaea, a model system used widely for the study of the fundamental mechanisms of learning and memory. We demonstrate cAMP response element (CRE)-binding activity in CNS protein extracts and show that one of the CRE-binding proteins is recognized by a polyclonal antibody raised to mammalian (human) CREB1. The same antibody detects specific CREB1 immunoreactivity in CNS extracts and in the nuclei of most neurons in the brain. Moreover, phospho-CREB1-specific immunoreactivity is increased significantly in protein extracts of the CNS by forskolin, an activator of adenylate cyclase. The forskolin-induced increase in phospho-CREB1 immunoreactivity is localized to the nuclei of CNS neurons, some of which have an important role in the formation of LTM. Significantly, classical food-reward conditioning increases phospho-CREB1 immunoreactivity in Lymnaea CNS protein extracts. This increase in immunoreactivity is specific to the ganglia that contain the feeding circuitry, which undergoes cellular changes after classical conditioning. This work establishes the expression of a highly conserved functional CREB1-like protein in the CNS of Lymnaea and opens the way for a detailed analysis of the role of CREB proteins in LTM formation in this model system.

Animals↗