Lymnaea stagnalis and the development of neuroelectronic technologies

The recent development of techniques for stimulating and recording from individual neurons grown on semiconductor chips has ushered in a new era in the field of neuroelectronics. Using this approach to construct complex neural circuits on silicon from individual neurons will require improvements at the neuron/semiconductor interface and advances in controlling synaptogenesis. Although devices incorporating vertebrate neurons may be an ultimate goal, initial investigations using neurons from the pond snail Lymnaea stagnalis have distinct advantages. Simple two-cell networks connected by electrical synapses have already been reconstructed on semiconductor chips. Furthermore, considerable progress has been made in controlling the processes that underlie chemical synapse formation in Lymnaea. Studies of Lymnaea neural networks on silicon chips will lead to a deeper understanding of the long-term dynamics of simple neural circuits and may provide the basis for reliable interfaces for new neuroprosthetic devices.     

Heterosynaptic metaplastic regulation of synaptic efficacy in CA1 pyramidal neurons of rat hippocampus

The induction threshold, and the magnitude and direction of changes in synaptic plasticity may depend on the previous history of neuronal activity. This phenomenon, termed "metaplasticity," could play an important role in integration processes by coordinating the modulation of synapses. Although metaplasticity has been analyzed extensively, its underlying cellular mechanisms remain largely unknown. Using in vitro electrophysiological and computer simulation approaches, we investigated the contribution of the slow Ca2+-dependent afterhyperpolarization (sAHP) in the metaplastic control of the induction of long-term potentiation (LTP) at convergent CA3-CA1 pyramidal neuron synapses. We report that classical conditioning protocols may lead to the simultaneous induction of a sustained homosynaptic LTP and a potentiation of the sAHP that endured approximately 1 h. The sAHP potentiation dramatically altered the spike responses of the CA1 pyramidal neuron. Of particular interest was the reduction of the CA1 neuron excitability and, consequently, of the capacity of a nonpotentiated synaptic input to elicit spikes while the sAHP was potentiated. This reduction in excitability temporarily prevented nonpotentiated synaptic inputs to exhibit an LTP induced by presynaptic tetanization. This metaplasticity was strongly resistant to increases in the magnitude of synaptic tetanization protocols. We propose that this heterosynaptic metaplasticity, mediated by intrinsic cellular mechanisms, triggered by brief periods of activity, and relying on changes of a slow Ca2+-activated K+ current, may contribute to adjusting the efficacy of synaptic connections and shaping network behavior to regulate integration processes.     

A semimechanistic and mechanistic population PK-PD model for biomarker response to ibandronate, a new bisphosphonate for the treatment of osteoporosis

AIMS: Ibandronate, a highly potent nitrogen-containing bisphosphonate, is the subject of an ongoing clinical development programme that aims to maximize the potential of simplified, less frequent oral and intravenous (i.v.) administration in osteoporosis. A modelling and simulation project was undertaken to characterize further the clinical pharmacology of ibandronate and identify convenient intermittent oral and i.v. regimens for clinical evaluation. METHODS AND RESULTS: Using selected data from clinical studies involving 174 women with postmenopausal osteoporosis (PMO), a classical multicompartmental pharmacokinetic-pharmacodynamic (PK-PD) model was developed that accurately described the PK of i.v. ibandronate in plasma and urine and urinary excretion of the C-telopeptide of the alpha chain of type I collagen (uCTX), a sensitive biomarker of PD response to ibandronate. To reduce processing times, the classical PK-PD model was simplified using a "kinetics of drug action" or kinetic (K)-PD model (i.e. a dose-response model as opposed to a dose-concentration-response model). The performance of the K-PD model was evaluated by fitting data simulated with the PK-PD model under various dosing regimens. The simplified model produced a virtually indistinguishable fit of the data from that of the PK-PD model. The K-PD model was extended to consider the influence of supplemental therapy (calcium with or without vitamin D) on the PD response and validated by retrospectively simulating the uCTX response in a prior Phase III and Phase II/III study of i.v. ibandronate, given once every 3 months, in 3380 women with PMO. The observed median uCTX responses at the scheduled assessment points in the completed studies were within the distribution of the simulated responses. The K-PD model for i.v. ibandronate was extended further to allow simultaneous fitting of uCTX responses after i.v. and oral administration in 676 postmenopausal women with osteoporosis, and validated by retrospectively simulating the data observed in a Phase I study of oral daily ibandronate in 180 women with PMO. The K-PD model adequately described the uCTX response after oral dosing. CONCLUSIONS: This validated K-PD model is currently being used to evaluate a range of novel intermittent oral and i.v. ibandronate regimens in an ongoing clinical development programme.     

Effects of data limitations when modeling fatal occupational injury rates

BACKGROUND: Occupational fatal injury rate studies are often based upon uncertain and variable data. The numerator in rate calculations is often obtained from surveillance systems that can understate the true number of deaths. Worker-years, the denominator in many occupational rate calculations, are frequently estimated from sources that exhibit different amounts of variability. METHODS: Effects of these data limitations on analyses of trends in occupational fatal injuries were studied using computer simulation. Fatality counts were generated assuming an undercount. Employment estimates were produced using two different strategies, reflecting either frequent but variable measurements or infrequent, precise estimates with interpolated estimates for intervening years. Poisson regression models were fit to the generated data. A range of empirically motivated fatality rate and employment parameters were studied. RESULTS: Undercounting fatalities resulted in biased estimation of the intercept in the Poisson regression model. Relative bias in the trend estimate was near zero for most situations, but increased when a change in fatality undercounting over time was present. Biases for both the intercept and trend were larger when small employment populations were present. Denominator options resulted in similar rate and trend estimates, except where the interpolated method did not capture true trends in employment. CONCLUSIONS: Data quality issues such as consistency of conditions throughout the study period and the size of population being studied affect the size of the bias in parameter estimation.     

Fielding incognito standardised patients as 'known' patients in a controlled trial in general practice

BACKGROUND: Incognito standardised patients (SPs) have only been used to represent new patients so far. The few trials with incognito SPs provide little detail on the method used for fielding them. OBJECTIVE: To establish the feasibility of introducing SPs as 'known' patients (i.e. patients who have previously visited the practice) into practices, to indicate the required practice preparations, and to describe the various aspects of using SPs in a pretest/post-test design. METHODS: We used incognito SPs as known patients in a controlled trial to assess the practice behaviour of 49 trainees. The SPs received a 2-day training in role playing and completing checklists. We compiled comprehensive practice information folders of each practice to be visited. Real personal data and faked medical data of SPs were inserted in the filing system of each practice to be visited. Apart from SP roles with slightly different reasons-for-encounter and different SPs, the same training protocol, checklists and practice information folders were used in the post-test. RESULTS: The SPs carried out 287 visits in 50 practices. All practices prepared the patient records for the SP visits in a fairly authentic practice style. Trainees detected the SP in 74 visits. The main reasons for detection were imperfections in patient records and aspects of SP roles or role playing. CONCLUSION: Fielding incognito SP visits as known patients was feasible but labour-intensive. Preparing the SP patient records and familiarising SPs with the interior of practices represented new elements in the use of SPs. The pretest/post-test format made their use more efficient instead of complicating it.     

Evaluation of a surgical simulator for learning clinical anatomy

BACKGROUND: New techniques in imaging and surgery have made 3-dimensional anatomical knowledge an increasingly important goal of medical education. This study compared the efficacy of 2 supplemental, self-study methods for learning shoulder joint anatomy to determine which method provides for greater transfer of learning to the clinical setting. METHODS: Two groups of medical students studied shoulder joint anatomy using either a second-generation virtual reality surgical simulator or images from a textbook. They were then asked to identify anatomical structures of the shoulder joint as they appeared in a videotape of a live arthroscopic procedure. RESULTS: The mean identification scores, out of a possible score of 7, were 3.1 +/- 1.3 for the simulator group and 2.9 +/- 1.5 for the textbook group (P = 0.70). Student ratings of the 2 methods on a 5-point Likert scale were significantly different. The simulator group rated the simulator more highly as an effective learning tool than the textbook group rated the textbook (means of 3.2 +/- 0.7 and 2.6 +/- 0.5, respectively, P = 0.02). Furthermore, the simulator group indicated that they were more likely to use the simulator as a learning tool if it were available to them than the textbook group was willing to use the textbook (means of 4.0 +/- 1.2 and 3.0 +/- 0.9, respectively, P = 0.02). CONCLUSION: Our results show that this surgical simulator is at least as effective as textbook images for learning anatomy and could enhance student learning through increased motivation. These findings provide insight into simulator development and strategies for learning anatomy. Possible explanations and future research directions are discussed.     

Performance-related stress symptoms in simulated patients

INTRODUCTION: During the first 4 years of the 6-year undergraduate medical curriculum at Maastricht University, the Netherlands, students practise clinical skills in simulated patient (SP) encounters at the Skillslab. Generally, these encounters are instructive and enjoyable for both students and SPs. However, in conversations with SP trainers, some SPs have mentioned experiencing adverse symptoms due to performing a patient role. Some published studies have reported similar findings in SPs. We explored the seriousness of this problem by surveying SPs on the occurrence and severity of stress symptoms related to performing patient roles. We also examined by which variables the symptoms were influenced. METHODS: An anonymous questionnaire was developed to investigate factors related to stress symptoms and the frequency and severity of stress symptoms. A burnout scale was also included in the questionnaire. All SPs who had performed between March 2000 and March 2001 were asked to participate. RESULTS: The response rate was 84%. Of the SPs, 73% were found to have experienced stress symptoms, with a mean of 4 symptoms per SP. No significant correlations were found between the occurrence of symptoms on the one hand and factors that might influence symptoms or the burnout scale on the other hand. DISCUSSION: An unexpectedly high number of SPs reported symptoms. Fortunately, the symptoms were relatively mild (2.2 on a 5-point scale). Future studies should address the connection between work as an SP and symptoms, and measures should be taken to prevent and treat the symptoms. Debriefing sessions might play a role in this respect.     

Loss to Follow-Up in Cohort Studies: How Much is Too Much?

Loss to follow-up is problematic in most cohort studies and often leads to bias. Although guidelines suggest acceptable follow-up rates, the authors are unaware of studies that test the validity of these recommendations. The objective of this study was to determine whether the recommended follow-up thresholds of 60-80% are associated with biased effects in cohort studies. A simulation study was conducted using 1000 computer replications of a cohort of 500 observations. The logistic regression model included a binary exposure and three confounders. Varied correlation structures of the data represented various levels of confounding. Differing levels of loss to follow-up were generated through three mechanisms: missing completely at random (MCAR), missing at random (MAR) and missing not at random (MNAR). The authors found no important bias with levels of loss that varied from 5 to 60% when loss to follow-up was related to MCAR or MAR mechanisms. However, when observations were lost to follow-up based on a MNAR mechanism, the authors found seriously biased estimates of the odds ratios with low levels of loss to follow-up. Loss to follow-up in cohort studies rarely occurs randomly. Therefore, when planning a cohort study, one should assume that loss to follow-up is MNAR and attempt to achieve the maximum follow-up rate possible.     

The effect of nontransmural necroses on epicardial potential maps during paced activation: a simulation study

A number of studies have indicated that epicardial potentials provide detailed spatiotemporal information about the spread of electrical activation within the ventricular wall. Here, we used a computer model to simulate activation sequences and corresponding epicardial potential maps in the ventricles damaged by localized necroses. Our findings agreed with those of experimental studies performed for epicardial pacing locus in a complete transient loss of one of the positive areas when the necrosis was located subepicardially, and in a transient gap in the expanding positive areas when the necrosis was located intramurally and subendocardially. This study--by systematically comparing simulated epicardial potential maps with those recorded on the exposed canine hearts--constitutes an important step in validation of our model.