Transferring an extremely premature infant to an extra-uterine life support system: a prospective view on the obstetric procedure.

To improve care for extremely premature infants, the development of an extrauterine environment for newborn development is being researched, known as Artificial Placenta and Artificial Womb (APAW) technology. APAW facilitates extended development in a liquid-filled incubator with oxygen and nutrient supply through an oxygenator connected to the umbilical vessels. This setup is intended to provide the optimal environment for further development, allowing further lung maturation by delaying gas exposure to oxygen. This innovative treatment necessitates interventions in obstetric procedures to transfer an infant from the native to an artificial womb, while preventing fetal-to-neonatal transition. In this narrative review we analyze relevant fetal physiology literature, provide an overview of insights from APAW studies, and identify considerations for the obstetric procedure from the native uterus to an APAW system. Lastly, this review provides suggestions to improve sterility, fetal and maternal well-being, and the prevention of neonatal transition.

Interprofessional Consensus Regarding Design Requirements for Liquid-Based Perinatal Life Support (PLS) Technology.

Liquid-based perinatal life support (PLS) technology will probably be applied in a first-in-human study within the next decade. Research and development of PLS technology should not only address technical issues, but also consider socio-ethical and legal aspects, its application area, and the corresponding design implications. This paper represents the consensus opinion of a group of healthcare professionals, designers, ethicists, researchers and patient representatives, who have expertise in tertiary obstetric and neonatal care, bio-ethics, experimental perinatal animal models for physiologic research, biomedical modeling, monitoring, and design. The aim of this paper is to provide a framework for research and development of PLS technology. These requirements are considering the possible respective user perspectives, with the aim to co-create a PLS system that facilitates physiological growth and development for extremely preterm born infants.

Quantitative Evaluation of Medial Temporal Lobe Morphology in Children with Febrile Status Epilepticus: Results of the FEBSTAT Study.

BACKGROUND AND PURPOSE: The pathogenesis of febrile status epilepticus is poorly understood, but prior studies have suggested an association with temporal lobe abnormalities, including hippocampal malrotation. We used a quantitative morphometric method to assess the association between temporal lobe morphology and febrile status epilepticus. MATERIALS AND METHODS: Brain MR imaging was performed in children presenting with febrile status epilepticus and control subjects as part of the Consequences of Prolonged Febrile Seizures in Childhood study. Medial temporal lobe morphologic parameters were measured manually, including the distance of the hippocampus from the midline, hippocampal height:width ratio, hippocampal angle, collateral sulcus angle, and width of the temporal horn. RESULTS: Temporal lobe morphologic parameters were correlated with the presence of visual hippocampal malrotation; the strongest association was with left temporal horn width (P < .001; adjusted OR, 10.59). Multiple morphologic parameters correlated with febrile status epilepticus, encompassing both the right and left sides. This association was statistically strongest in the right temporal lobe, whereas hippocampal malrotation was almost exclusively left-sided in this cohort. The association between temporal lobe measurements and febrile status epilepticus persisted when the analysis was restricted to cases with visually normal imaging findings without hippocampal malrotation or other visually apparent abnormalities. CONCLUSIONS: Several component morphologic features of hippocampal malrotation are independently associated with febrile status epilepticus, even when complete hippocampal malrotation is absent. Unexpectedly, this association predominantly involves the right temporal lobe. These findings suggest that a spectrum of bilateral temporal lobe anomalies are associated with febrile status epilepticus in children. Hippocampal malrotation may represent a visually apparent subset of this spectrum.

The use of intraoperative parathyroid hormone monitoring in minimally invasive parathyroid surgery.

Introduction Surgery is the first-line management option for patients with primary hyperparathyroidism (pHPT). Minimally invasive parathyroidectomy (MIP) is now preferable but few centres offer this service, mainly because of lack of intraoperative parathyroid hormone (IOPTH) testing. The aim of this study was to identify whether the measurement of IOPTH in patients having minimally invasive parathyroidectomy for pHPT alters their management. Methods A retrospective review was carried out of 78 consecutive patients who underwent parathyroid surgery by a single surgeon with a special interest in parathyroid surgery. The clinical impact of IOPTH monitoring was recorded postoperatively in a timely manner. Serum adjusted calcium levels were checked preoperatively (on admission) and one month postoperatively; normalisation was considered a cure. Results In the setting of curative MIP, IOPTH measurement did not influence the management in any of the patients but it could have led to bilateral parathyroid exploration (BPE) in three instances. Similarly, in cases that required lengthening of the MIP incision, IOPTH results did not influence patient management although it could have led to BPE in one case. Conclusion MIP offers an effective cure for patients with hyperparathyroidism. The addition of IOPTH testing adds increased expense, operating time and risk to patients otherwise suitable for MIP.

The structure of networks that produce the transformation from grid cells to place cells.

Since grid cells were discovered in the medial entorhinal cortex, several models have been proposed for the transformation from periodic grids to the punctate place fields of hippocampal place cells. These prior studies have each focused primarily on a particular model structure. By contrast, the goal of this study is to understand the general nature of the solutions that generate the grids-to-places transformation, and to exploit this insight to solve problems that were previously unsolved. First, we derive a family of feedforward networks that generate the grids-to-places transformations. These networks have in common an inverse relationship between the synaptic weights and a grid property that we call the normalized offset. Second, we analyze the solutions of prior models in terms of this novel measure and found to our surprise that almost all prior models yield solutions that can be described by this family of networks. The one exception is a model that is unrealistically sensitive to noise. Third, with this insight into the structure of the solutions, we then construct explicitly solutions for the grids-to-places transformation with multiple spatial maps, that is, with place fields in arbitrary locations either within the same (multiple place fields) or in different (global remapping) enclosures. These multiple maps are possible because the weights are learned or assigned in such a way that a group of weights contributes to spatial specificity in one context but remains spatially unstructured in another context. Fourth, we find parameters such that global remapping solutions can be found by synaptic learning in spiking neurons, despite previous suggestions that this might not be possible. In conclusion, our results demonstrate the power of understanding the structure of the solutions and suggest that we may have identified the structure that is common to all robust solutions of the grids-to-places transformation.

[Laboratory input. General practitioners positive about reflective testing]. / Eigen inbreng van het laboratorium. Huisartsen positief over 'reflecterend testen'.

OBJECTIVE: To investigate the opinion of general practitioners on reflective testing, i.e. the practice of additional tests being performed and comments added to the results by laboratory staff when appropriate. DESIGN: Descriptive. METHOD: In the eastern South Limburg region 155 general practitioners received a list of 10 fictitious patient cases, each involving the possible addition of a specific test. The general practitioners could choose what they preferred the laboratory to do: add tests, phone the general practitioner, add a written comment or do nothing. In addition the general practitioners were asked to judge the effect of additional tests and comments on patient management with respect to diagnosis, treatment and referral, using 200 laboratory reports from their own patients. RESULTS: The response to the fictitious cases was 45%. Most general practitioners favoured the laboratory taking the initiative by adding on tests and commenting on the results in the given clinical scenarios. 78% of the questionnaires accompanying the lab reports were returned by 87% of the general practitioners. In nearly all cases (99%) the service was marked as useful. In more than half of the cases (53%) reflective testing affected the measures taken by the general practitioners. CONCLUSION: Reflective testing was in general welcomed by the general practitioners. In the majority of cases this led to an improvement in the diagnosis or adjustment of treatment.

Phenomenology of prolonged febrile seizures: results of the FEBSTAT study.

BACKGROUND: Febrile status epilepticus (FSE) has been associated with hippocampal injury and subsequent mesial temporal sclerosis and temporal lobe epilepsy. However, little is known about the semiology of FSE. METHODS: A prospective, multicenter study of the consequences of FSE included children, aged 1 month through 5 years, presenting with a febrile seizure lasting 30 minutes or more. Procedures included neurologic history and examination and an MRI and EEG within 72 hours. All information related to seizure semiology was reviewed by three epileptologists blinded to MRI and EEG results and to subsequent outcome. Inter-rater reliability was assessed by the kappa statistic. RESULTS: Among 119 children, the median age was 1.3 years, the mean peak temperature was 103.2 degrees F, and seizures lasted a median of 68.0 minutes. Seizure duration followed a Weibull distribution with a shape parameter of 1.68. Seizures were continuous in 52% and behaviorally intermittent (without recovery in between) in 48%; most were partial (67%) and almost all (99%) were convulsive. In one third of cases, FSE was unrecognized in the emergency department. Of the 119 children, 86% had normal development, 24% had prior febrile seizures, and family history of febrile seizures in a first-degree relative was present in 25%. CONCLUSIONS: Febrile status epilepticus is usually focal and often not well recognized. It occurs in very young children and is usually the first febrile seizure. Seizures are typically very prolonged and the distribution of seizure durations suggests that the longer a seizure continues, the less likely it is to spontaneously stop.

A Bayesian decoding algorithm for analysis of information encoding in neural ensembles.

Developing optimal strategies for constructing and testing decoding algorithms is an important question in computational neuroscience, In this field, decoding algorithms are mathematical methods that model ensemble neural spiking activity as they dynamically represent a biological signal. We present a recursive decoding algorithm based on a Bayesian point process model of individual neuron spiking activity and a linear stochastic state-space model of the biological signal. We assess the accuracy of the algorithm by computing, along with the decoding error, the true coverage probability of the approximate 0.95 confidence regions for the individual signal estimates. We illustrate the new algorithm by analyzing the position and ensemble neural spiking activity of CA1 hippocampal neurons from a rat foraging in an open circular environment The median decoding error during 10 minutes of open foraging was 5.5 cm, and the true coverage probability for 0.95 confidence regions was 0.75 using 32 neurons. These findings improve significantly on our previous results and suggest an approach to reading dynamically information represented in ensemble neural spiking activity.

Children's ibuprofen suspension for the acute treatment of pediatric migraine.

OBJECTIVE: To compare the efficacy of a single over-the-counter dose (7.5 mg/kg, p.o.) of children's ibuprofen suspension vs. placebo for the acute treatment of pediatric migraine. BACKGROUND: Migraine occurs in 4% of young children. There is a paucity of controlled clinical research in the treatment of childhood migraine and there are currently no approved drugs in the USA for treatment of migraine in children < or = 12 years of age. The purpose of this study is to assess the efficacy and tolerability of a single OTC dose of ibuprofen suspension for the acute treatment of childhood migraine. METHODS: Prospective, double-blind, placebo-controlled, parallel group, randomized study of children 6-12 yrs with migraine (I.H.S.-R 1997) treating 1 attack with a 7.5 mg/kg liq. ibuprofen vs matching placebo. Efficacy measures: (1). Headache severity based upon a 4 pt scale (severe, mod., mild, no headache) at 30, 60, 90, 120, 180 and 240 minutes post dose, and (2). nausea, vomiting, and photo/phonophobia at 120 min. The 1 degrees endpoint was cumulative % of responders (severe or mod. headache reduced to mild or none) by 120 minutes. Secondary endpoints were headache recurrence within 4-24 hours and need for rescue medicines within 4 hours. RESULTS: 138 enrolled; 84 treated/completed diary. 45 active agent, 39 placebo. The 2 groups were comparable (active: placebo) - Ages: 9: 9.1, gender boy/girl - 1.25: 1.6, and diagnosis: migraine w/o aura - 86%: 79%. Concomitant use of prophylactic Rx: 24%: 10% (Table 3). Nausea was eliminated in 60% of the ibuprofen treated patients and 39% of the placebo group (p<0.001). Vomiting, photophobia and phonophobia had marginal, but not statistically significant, decreases at 2 hours. A striking gender difference was noted (Table 4): No AE's were reported. CONCLUSION: Children's ibuprofen suspension at an OTC dose of 7.5 mg/kg is an effective and well-tolerated agent for pain relief in the acute treatment of childhood migraine, particularly in boys. There is a striking difference in gender response rates and placebo responder rates between girls and boys. The boys responded at a statistically significant rate, and girls failed to do so because of a very high placebo responder rate. Multi-center trials are recommended.

An analysis of neural receptive field plasticity by point process adaptive filtering.

Neural receptive fields are plastic: with experience, neurons in many brain regions change their spiking responses to relevant stimuli. Analysis of receptive field plasticity from experimental measurements is crucial for understanding how neural systems adapt their representations of relevant biological information. Current analysis methods using histogram estimates of spike rate functions in nonoverlapping temporal windows do not track the evolution of receptive field plasticity on a fine time scale. Adaptive signal processing is an established engineering paradigm for estimating time-varying system parameters from experimental measurements. We present an adaptive filter algorithm for tracking neural receptive field plasticity based on point process models of spike train activity. We derive an instantaneous steepest descent algorithm by using as the criterion function the instantaneous log likelihood of a point process spike train model. We apply the point process adaptive filter algorithm in a study of spatial (place) receptive field properties of simulated and actual spike train data from rat CA1 hippocampal neurons. A stability analysis of the algorithm is sketched in the. The adaptive algorithm can update the place field parameter estimates on a millisecond time scale. It reliably tracked the migration, changes in scale, and changes in maximum firing rate characteristic of hippocampal place fields in a rat running on a linear track. Point process adaptive filtering offers an analytic method for studying the dynamics of neural receptive fields.

A comparison of the firing properties of putative excitatory and inhibitory neurons from CA1 and the entorhinal cortex.

The superficial layers of the entorhinal cortex (EC) provide the majority of the neocortical input to the hippocampus, and the deep layers of the EC receive the majority of neocortically bound hippocampal outputs. To characterize information transmission through the hippocampal and EC circuitry, we recorded simultaneously from neurons in the superficial EC, the CA1 region of hippocampus, and the deep EC while rodents ran for food reward in two environments. Spike waveform analysis allowed us to classify units as fast-spiking (FS) putative inhibitory cells or putative excitatory (PE) cells. PE and FS units' firing were often strongly correlated at short time scales, suggesting the presence a monosynaptic connection from the PE to FS units. EC PE units, unlike those found in CA1, showed little or no tendency to fire in bursts. We also found that the firing of FS and PE units from all regions was modulated by the approximately 8 Hz theta rhythm, although the firing of deep EC FS units tended to be less strongly modulated than that of the other types of units. When we examined the spatial specificity of FS units, we determined that FS units in all three regions showed low specificity. At the same time, retrospective coding, in which firing rates were related to past position, was present in FS units from all three regions and deep EC FS units often fired in a "path equivalent" manner in that they were active in physically different, but behaviorally related positions both within and across environments. Our results suggest that while the firing of FS units from CA1 and the EC show similarly low levels of position specificity, FS units from each region differ from one another in that they mirrored the associated PE units in terms of their tendency to show more complex positional firing properties like retrospective coding and path equivalence.

Construction and analysis of non-Poisson stimulus-response models of neural spiking activity.

A paradigm for constructing and analyzing non-Poisson stimulus-response models of neural spike train activity is presented. Inhomogeneous gamma (IG) and inverse Gaussian (IIG) probability models are constructed by generalizing the derivation of the inhomogeneous Poisson (IP) model from the exponential probability density. The resultant spike train models have Markov dependence. Quantile-quantile (Q-Q) plots and Kolmogorov-Smirnov (K-S) plots are developed based on the rate-rescaling theorem to assess model goodness-of-fit. The analysis also expresses the spike rate function of the neuron directly in terms of its interspike interval (ISI) distribution. The methods are illustrated with an analysis of 34 spike trains from rat CA1 hippocampal pyramidal neurons recorded while the animal executed a behavioral task. The stimulus in these experiments is the animal's position in its environment and the response is the neural spiking activity. For all 34 pyramidal cells, the IG and IIG models gave better fits to the spike trains than the IP. The IG model more accurately described the frequency of longer ISIs, whereas the IIG model gave the best description of the burst frequency, i.e. ISIs < or = 20 ms. The findings suggest that bursts are a significant component of place cell spiking activity even when position and the background variable, theta phase, are taken into account. Unlike the Poisson model, the spatial and temporal rate maps of the IG and IIG models depend directly on the spiking history of the neurons. These rate maps are more physiologically plausible since the interaction between space and time determines local spiking propensity. While this statistical paradigm is being developed to study information encoding by rat hippocampal neurons, the framework should be applicable to stimulus-response experiments performed in other neural systems.

Trajectory encoding in the hippocampus and entorhinal cortex.

We recorded from single neurons in the hippocampus and entorhinal cortex (EC) of rats to investigate the role of these structures in navigation and memory representation. Our results revealed two novel phenomena: first, many cells in CA1 and the EC fired at significantly different rates when the animal was in the same position depending on where the animal had come from or where it was going. Second, cells in deep layers of the EC, the targets of hippocampal outputs, appeared to represent the similarities between locations on spatially distinct trajectories through the environment. Our findings suggest that the hippocampus represents the animal's position in the context of a trajectory through space and that the EC represents regularities across different trajectories that could allow for generalization across experiences.

Adjunctive therapy with oxcarbazepine in children with partial seizures. The Oxcarbazepine Pediatric Study Group.

OBJECTIVE: To evaluate the safety and efficacy of oxcarbazepine (OXC) as adjunctive therapy in children with inadequately controlled partial seizures on one or two concomitant antiepileptic drugs (AEDs). BACKGROUND: OXC has shown antiepileptic activity in several comparative monotherapy trials in newly diagnosed patients with epilepsy, and in a placebo-controlled monotherapy trial in hospitalized patients evaluated for epilepsy surgery. DESIGN: A total of 267 patients were evaluated in a multicenter, randomized, placebo-controlled trial consisting of three phases: 1) a 56-day baseline phase (patients maintained on their current AEDs); 2) a 112-day double-blind treatment phase (patients received either OXC 30-46 mg/kg/day orally or placebo); and 3) an open-label extension phase. Data are reported only from the double-blind treatment phase; the open-label extension phase is ongoing. METHODS: Children (3 to 17 years old) with inadequately controlled partial seizures (simple, complex, and partial seizures evolving to secondarily generalized seizures) were enrolled. RESULTS: Patients treated with OXC experienced a significantly greater median percent reduction from baseline in partial seizure frequency than patients treated with placebo (p = 0.0001; 35% versus 9%, respectively). Forty-one percent of patients treated with OXC experienced a > or =50% reduction from baseline in partial seizure frequency per 28 days compared with 22% of patients treated with placebo (p = 0.0005). Ninety-one percent of the group treated with OXC and 82% of the group treated with placebo reported > or =1 adverse event; vomiting, somnolence, dizziness, and nausea occurred more frequently (twofold or greater) in the group treated with OXC. CONCLUSION: OXC adjunctive therapy administered in a dose range of 6 to 51 mg/kg/day (median 31.4 mg/kg/day) is safe, effective, and well tolerated in children with partial seizures.

Lamictal (lamotrigine) monotherapy for typical absence seizures in children.

PURPOSE: To investigate whether lamotrigine (LTG) monotherapy is effective and safe for newly diagnosed typical absence seizures in children and adolescents (aged 3-15 years, n = 45). METHODS: A "responder-enriched" study design was used: open-label dose escalation was followed by placebo-controlled, double-blind testing of LTG. Conventional hyperventilation testing with EEG recording was used to confirm diagnoses and assess treatment success defined as complete freedom from seizures. Ambulatory 24-h EEG recordings provided supporting evidence of effectiveness. Safety was assessed by evaluation of adverse events, vital signs, and physical, neurologic, and laboratory examinations. Plasma samples were taken to evaluate the pharmacokinetics of LTG. RESULTS: During initial open-label dose escalation, 71.4% of patients (intent-to-treat) or 82% (per protocol analysis) became seizure free; individual patients responded at doses ranging from 2 to 15 mg/kg/day (median, 5.0). In the placebo-controlled, double-blind phase of the study, statistically significantly more patients remained seizure free when treated with LTG (62%) than with placebo (21%; p < 0.02; for the intent-to-treat analysis). Mean plasma concentrations of LTG, were linearly related to dose, although there was substantial interindividual variation. No patients were withdrawn from the study for any safety-related reason. CONCLUSIONS: LTG monotherapy is effective for typical absence seizures in children and is generally well tolerated.

A statistical paradigm for neural spike train decoding applied to position prediction from ensemble firing patterns of rat hippocampal place cells.

The problem of predicting the position of a freely foraging rat based on the ensemble firing patterns of place cells recorded from the CA1 region of its hippocampus is used to develop a two-stage statistical paradigm for neural spike train decoding. In the first, or encoding stage, place cell spiking activity is modeled as an inhomogeneous Poisson process whose instantaneous rate is a function of the animal's position in space and phase of its theta rhythm. The animal's path is modeled as a Gaussian random walk. In the second, or decoding stage, a Bayesian statistical paradigm is used to derive a nonlinear recursive causal filter algorithm for predicting the position of the animal from the place cell ensemble firing patterns. The algebra of the decoding algorithm defines an explicit map of the discrete spike trains into the position prediction. The confidence regions for the position predictions quantify spike train information in terms of the most probable locations of the animal given the ensemble firing pattern. Under our inhomogeneous Poisson model position was a three to five times stronger modulator of the place cell spiking activity than theta phase in an open circular environment. For animal 1 (2) the median decoding error based on 34 (33) place cells recorded during 10 min of foraging was 8.0 (7.7) cm. Our statistical paradigm provides a reliable approach for quantifying the spatial information in the ensemble place cell firing patterns and defines a generally applicable framework for studying information encoding in neural systems.

Spin-spin relaxation of brain tissues in systemic lupus erythematosus. A method for increasing the sensitivity of magnetic resonance imaging for neuropsychiatric lupus.

OBJECTIVE: To correlate the spin-spin relaxation time (T2) of brain tissue in neuropsychiatric systemic lupus erythematosus (NPSLE) with the patient's clinical condition. METHODS: T2 values were determined in 54 SLE patients and 45 non-SLE controls at 1.5 Tesla, using intensity from multi-echo magnetic resonance (MR) images fitted to an exponential decay curve with rate-constant T2. RESULTS: The T2 of white matter was increased in SLE patients compared with controls (P = 0.01) and was increased in those patients who had previously experienced major NPSLE: Patients with acute diffuse neurologic manifestations (seizures, psychosis, coma) demonstrated a longer T2 of the gray matter (mean +/- SD 92.75 +/- 6.35 ms, n = 10) than did other SLE patients (mean +/- SD 79.61 +/- 5.04 ms, n = 44) (P = 0.02 by t-test), which suggests acute cerebral edema. The mean T2 values of reversible and nonreversible focal lesions were significantly different (P < 0.02), indicating different microenvironments and micropathology. CONCLUSION: Quantitative T2 measurement extends the utility and sensitivity of conventional MR imaging for evaluating NPSLE:

Congenital malformations and psychosocial development in children conceived by in vitro fertilization.

To determine whether in vitro fertilization (IVF) as a method of conception is associated with an increased risk for congenital malformations or developmental dysfunction, we performed a general physical examination for malformations, neurologic examination, developmental examination (Bayley Scales), echocardiography, electrocardiography, abdominal ultrasound study, and, when possible, cranial ultrasound examination on a cohort of 83 IVF children and 93 matched non-IVF children. Major malformations were found in two IVF and one non-IVF subject; the rates were not significantly different. The mean Mental Development Index scores for IVF subjects and the comparison group were 115 +/- 13 and 111 +/- 13, respectively (p = 0.12). The mean Psychomotor Development Index scores were 114 +/- 14 and 108 +/- 15 (p = 0.04). Based on these small numbers but extensive evaluation, we found no association between conception by IVF and an increased risk for congenital malformations. Likewise, children conceived by IVF showed no evidence of developmental delay. Their high average achievement on the Bayley tests probably resulted from the exceptional motivation of their parents ("wantedness") and their generally high socioeconomic status.