Agreement and disagreement in pediatric functional neurological symptom disorders: Comparing patient reported outcome measures (PROMs) and clinician assessments.

Youth with functional neurological symptom disorder (FNSD) often perceive themselves as having limited capabilities, which may not align with clinical evaluations. This study assessed the disparities between clinician evaluations and patient-reported outcome measures (PROMs) regarding pain, motor function, and learning difficulties in youth with FNSD. Sixty-two youths with FNSD participated in this study, all of whom reported experiencing pain, motor problems, and/or learning difficulties. Clinicians also assessed these domains, resulting in a two-by-two categorization matrix: (1) agreement: child and clinician report "problems"; (2) agreement: child and clinician report "no problems"; (3) disagreement: child reports "problems" while the clinician does not; and (4) disagreement: clinician reports "problems" while the child does not. Agreement/disagreement differences were analyzed. No significant differences in prevalence were observed between the evaluators regarding pain (clinician-85%, child-88%), motor (clinician-98%, child-95%), or learning problems (clinician-69%, child-61%). More than 80% of the children and clinicians report pain and motor disorders. Instances in which children and clinicians reported learning problems (40.3%) exceeded cases in which both reported no problems (9.6%) or only the child reported problems (20.9%). Overall, the agreement between pain and motor function assessments was high (>90%), whereas that concerning learning difficulties was moderate (49.9%). Disagreement in pain/motor assessments was minimal (<5%), whereas for learning difficulties, disagreement rates were high (>20%). In conclusion, a significant concordance exists between PROMs and clinician assessments of pain and motor problems. However, the higher frequency of disagreements regarding learning difficulties emphasizes the importance of incorporating patient and clinician evaluations in pediatric FNSD treatment.

FMF - clinical features, new treatments and the role of genetic modifiers: a critical digest of the 2010-2012 literature.

The last two years have been marked by many studies trying to better characterize the clinical features of FMF in children and proposal of new treatment for those who are resistant to colchicine. In addition, many studies tried to address the potential effect of genetic modifiers on FMF and the potential effect of MEFV mutations on other inflammatory diseases. The main points arose from these studies include a breakthrough in the therapeutic approach for FMF and the lack of consistency regarding the reciprocal effect of MEFV mutations on other diseases and the effect of genetic modifiers on FMF. The highlights of these studies, their potential clinical implications and the unmet needs, which are still to be addressed, are summarised in this review.

Superantigen binding to a T cell receptor beta chain of known three-dimensional structure.

The three-dimensional structure of an unglycosylated T cell antigen receptor (TCR) beta chain has recently been determined to 1.7 A resolution. To investigate whether this soluble beta chain (murine V beta 8.2J beta 2.1C beta 1) retains superantigen (SAG)-binding activity, we measured its affinity for various bacterial SAGs in the absence of MHC class II molecules. Dissociation constants (KDs) were determined using two independent techniques: surface plasmon resonance detection and sedimentation equilibrium. Specific binding was demonstrated to staphylococcal enterotoxins (SEs) B, C1, C2, and C3 and to streptococcal pyrogenic exotoxin A (SPEA), consistent with the known proliferative effects of these SAGs on T cells expressing V beta 8.2. In contrast, SEA, which does not stimulate V beta 8.2-bearing cells, does not bind the recombinant beta chain. Binding of the beta chain to SAGs was characterized by extremely fast dissociation rates (> 0.1 s-1), similar to those reported for certain leukocyte adhesion molecules. Whereas the beta chain bound SEC1, 2, and 3 with KDs of 0.9-2.5 microM, the corresponding value for SEB was approximately 140 microM. The much weaker binding to SEB than to SEC1, 2, or 3 was surprising, especially since SEB was found to actually be 3- to 10-fold more effective, on a molar basis, than the other toxins in stimulating the parental T cell hybridoma. We interpret these results in terms of the ability of SEC to activate T cells independently of MHC, in contrast to SEB. We have also measured SE binding to the glycosylated form of the beta chain and found that carbohydrate apparently does not contribute to recognition, even though the N-linked glycosylation sites at V beta 8.2 residues Asn24 and Asn74 are at or near the putative SAG-binding site. This result, along with the structural basis for the V beta specificity of SEs, are discussed in relation to the crystal structure of the unglycosylated beta chain.

A behavioral homeostasis theory of habituation and sensitization: II. Further developments and predictions.

Habituation may be viewed as a decremental behavioral change to iterative stimuli of little immediate relevance. It is observed from protozoa to humans, indicating its evolutionary significance. If habituation is interpreted as the process of filtering out unimportant repetitive stimuli, then how should sensitization be interpreted? The 'behavioral homeostasis theory' of these two behaviors is based on the notion that organisms at a high level of 'alertness' prior to experiencing a new iterative stimulus will show a large initial response followed by a decrement (habituation) if the stimulus is of little significance. Conversely, the same organism at a low level of 'alertness' will show a small initial response to the same stimulus followed by an increase in 'alertness' and a larger response to the next stimulus (sensitization) in order to receive enough information to assess its significance. Circadian rhythmicity is hypothesized to play a role in determining 'alertness' to a new iterative stimulus at any given time. The level of responsiveness in initial habituaters and sensitizers, as an asymptote is approached, is a balance between being too 'alert' to an unimportant stimulus and missing other significant stimuli, and being too 'un-alert' and missing a change in the relevance of the present iterative stimulus. The concept of 'behavioral homeostasis' includes behaviors beyond habituation and sensitization across phylogeny. It includes instinctive as well as learned, and group as well as individual behavior. Such behavioral homeostatic processes to optimize detection and assessment of constantly occurring external stimuli are critical for organism survival. Clinical implications of this theory are also examined.

Structure and control of pyridoxal phosphate dependent allosteric threonine deaminase.

BACKGROUND: Feedback inhibition of biosynthetic threonine deaminase (TD) from Escherichia coli provided one of the earliest examples of protein-based metabolic regulation. Isoleucine, the pathway end-product, and valine, the product of a parallel pathway, serve as allosteric inhibitor and activator, respectively. This enzyme is thus a useful model system for studying the structural basis of allosteric control mechanisms. RESULTS: We report the crystal structure of TD at 2.8 A resolution. The tetramer has 222 symmetry, with C-terminal regulatory domains projecting out from a core of catalytic PLP-containing N-terminal domains. The subunits, and especially the regulatory domains, associate extensively to form dimers, which associate less extensively to form the tetramer. Within the dimer, each monomer twists approximately 150 degrees around a thin neck between the domains to place its catalytic domain adjacent to the regulatory domain of the other subunit. CONCLUSIONS: The structure of TD and its comparison with related structures and other data lead to the tentative identification of the regulatory binding site and revealed several implications for the allosteric mechanism. This work prepares the way for detailed structure/function studies of the complex allosteric behaviour of this enzyme.

An exploration of how to define and measure the evolution of behavior, learning, memory and mind across the full phylogenetic tree of life.

There are probably few terms in evolutionary studies regarding neuroscience issues that are used more frequently than 'behavior', 'learning', 'memory', and 'mind'. Yet there are probably as many different meanings of these terms as there are users of them. Further, investigators in such studies, while recognizing the full phylogenetic spectrum of life and the evolution of these phenomena, rarely go beyond mammals and other vertebrates in their investigations; invertebrates are sometimes included. What is rarely taken into consideration, though, is that to fully understand the evolution and significance for survival of these phenomena across phylogeny, it is essential that they be measured and compared in the same units of measurement across the full phylogenetic spectrum from aneural bacteria and protozoa to humans. This paper explores how these terms are generally used as well as how they might be operationally defined and measured to facilitate uniform examination and comparisons across the full phylogenetic spectrum of life. This paper has 2 goals: (1) to provide models for measuring the evolution of 'behavior' and its changes across the full phylogenetic spectrum, and (2) to explain why 'mind phenomena' cannot be measured scientifically at the present time.

Biological function made crystal clear - annotation of hypothetical proteins via structural genomics.

Many of the gene products of completely sequenced organisms are 'hypothetical' - they cannot be related to any previously characterized proteins - and so are of completely unknown function. Structural studies provide one means of obtaining functional information in these cases. A 'structural genomics' project has been initiated aimed at determining the structures of 50 hypothetical proteins from Haemophilus influenzae to gain an understanding of their function. Each stage of the project - target selection, protein production, crystallization, structure determination, and structure analysis - makes use of recent advances to streamline procedures. Early results from this and similar projects are encouraging in that some level of functional understanding can be deduced from experimentally solved structures.

Habituation and sensitization in an aneural cell: some comparative and theoretical considerations.

Several shorter- and longer-term non-associative modifications in behavior are known to occur in neural as well as aneural systems. Thus neural investment is not essential for these phenomena to occur. Cellular studies of these behaviors in Protozoa, where a single cell is also a whole organism, may be useful in investigating the evolution of mechanisms underlying these plastic behavioral changes.

Advanced coronary artery disease: Appropriate end points for trials of novel therapies.

BACKGROUND: The segment of patients with advanced coronary artery disease, or disease that is not amenable to conventional revascularization therapies, continues to grow. Because the natural history of these patients is less defined, the appropriate end points for trials of novel revascularization therapies involving patients with advanced coronary artery disease are not certain. METHODS AND RESULTS: The Mediators of Social Support Study (MOSS) prospectively followed up outcomes of long-term survival, quality of life, resource use, and costs for 1189 patients and compared outcomes of patients with advanced coronary artery disease with those of a reference group who underwent bypass surgery or angioplasty. CONCLUSIONS: Despite greater disease burden, cost, and mortality for patients with advanced coronary artery disease, a number of self-reported measures of general health status improved in a similar fashion to that of patients eligible for angioplasty or bypass surgery. These findings should inform the design of trials involving novel therapies, suggesting that angina status and mortality be included as primary end points in the consideration of efficacy. This work also suggests that additional studies of novel therapies involving larger sample sizes may be required to confidently characterize efficacy.

Evaluation of the growth hormone exercise test in normal and growth hormone-deficient children.

A group of 168 short but otherwise normal children (group A) and 25 children deficient in growth hormone (GH) (group B) wwere studied with an exercise stimulation test to determine the expected error of this method. In group A, 125 (74.4%) had maximum GH responses greater than 15 ng/ml, 23 (13.7%) had responses between 10 and 15 ng/ml, and 20 (11.9%) had responses less than 10 ng/ml. The mean +/- SD values were 8.4 +/- 0.4 ng/ml at 0 time, 26.3 +/- 15.0 at 20 minutes, and 10.7 +/- 8.3 at 40 minutes. The mean maximum response was 27.7 +/- 14.3 ng/ml. In group B, 22 (88%) had maximum responses less than 10 ng/ml and 3 (12%) had responses between 10 and 15 ng/ml. Patients with maximum responses less than 10 ng/ml have a high probability of being GH-deficinet, whereas patients with responses between 10 and 15 ng/ml are less likely to be GH-deficient. No patients with responses greater than 15 ng/ml were GH-deficient.

The ABRF-MIRG'02 study: assembly state, thermodynamic, and kinetic analysis of an enzyme/inhibitor interaction.

Fully characterizing the interactions involving biomolecules requires information on the assembly state, affinity, kinetics, and thermodynamics associated with complex formation. The analytical technologies often used to measure biomolecular interactions include analytical ultracentrifugation (AUC), isothermal titration calorimetry (ITC), and surface plasmon resonance (SPR). In order to evaluate the capabilities of core facilities to implement these technologies, the Association of Biomolecular Resource Facilities (ABRF) Molecular Interactions Research Group (MIRG) developed a standardized model system and distributed it to a panel of AUC, ITC, and SPR operators. The model system was composed of a well-characterized enzyme-inhibitor pair, namely bovine carbonic anhydrase II (CA II) and 4-carboxybenzenesulfonamide (CBS). Study participants were asked to measure one or more of the following: (1) the molecular mass, homogeneity, and assembly state of CA II by AUC; (2) the affinity and thermodynamics for complex formation by ITC; and (3) the affinity and kinetics of complex formation by SPR. The results from this study provide a benchmark for comparing the capabilities of individual laboratories and for defining the utility of the different instrumentation.

Cost effectiveness of inpatient initiation of antiarrhythmic therapy for supraventricular tachycardias.

This study assessed the cost effectiveness of inpatient antiarrhythmic therapy initiation for supraventricular tachycardias using a metaanalysis of proarrhythmic risk and a decision analysis that compared inpatient to outpatient therapy initiation. A MEDLINE search of trials of antiarrhythmic therapy for supraventricular tachycardias was performed, and episodes of cardiac arrest, sudden or unexplained death, syncope, and sustained or unstable ventricular arrhythmias were recorded. A weighted average event rate, by sample size, was calculated and applied to a clinical decision model of therapy initiation in which patients were either hospitalized for 72 hours or treated as outpatients. Fifty-seven drug trials involving 2,822 patients met study criteria. Based on a 72-hour weighted average event rate of 0.63% (95% confidence interval, 0.2% to 1.2%), inpatient therapy initiation cost $19,231 per year of life saved for a 60-year-old patient with a normal life expectancy. Hospitalization remained cost effective when event rates and life expectancies were varied to model hypothetical clinical scenarios. For example, cost-effectiveness ratios for a 40-year-old without structural heart disease and a 60-year-old with structural heart disease were $37,510 and $33,310, respectively, per year of life saved. Thus, a 72-hour hospitalization for antiarrhythmic therapy initiation is cost effective for most patients with supraventricular tachycardias.

An evaluation of factors influencing Bayesian learning systems.

OBJECTIVES: To examine the influences of situational and model factors on the accuracy of Bayesian learning systems. DESIGN: This study examines the impacts of variations in two situational factors, training sample size and number of attributes, and in two model factors, choice of Bayesian model and criteria for excluding model attributes, on the overall accuracy of Bayesian learning systems. MEASUREMENTS: The test data were derived from myocardial infarction patients who were admitted to eight hospitals in New Orleans during 1985. The test sample consisted of 339 cases; the training samples included 100, 400, and 800 cases. APACHE II variables were used for the model attributes and patient discharge status as the outcome predicted. Attribute sets were selected in sizes of 4, 8, and 12. The authors varied the Bayesian models (proper and simple) and the attribute exclusion criteria (optimism and pessimism). RESULTS: The simple Bayes model, which assumes conditional independence, consistently equalled or outperformed the proper (maximally dependent) Bayes model, which assumes conditional dependence, across all training sample and attribute set sizes. Not excluding model attributes was found to be preferable to using sample theory as an attribute exclusion criterion in both the simple and the proper models. CONCLUSION: In the domain tested, the simple Bayes model with optimistic exclusion is more robust than previously assumed and increasing the number of attributes in a model had a greater relative impact on model accuracy than did increasing the number of training sample cases. Assessment of applicability of these findings to other domains will require further study. In addition, other models that are between these two extremes must be investigated. These include models that approximate proper Bayes' conditional dependence computations while requiring fewer training sample cases, attribute exclusion criteria between optimism and pessimism that improve accuracy, and ordering techniques for introducing attributes into Bayes models that optimize the information value associated with the attributes in test-sample cases.

Selecting a model system for neurobiological studies of learning and memory.

This article discusses the logic underlying the use of invertebrate model systems for investigating the neurobiological basis of learning and memory, the kinds of questions which can be asked of these systems as well as their limitations. A model system selected to answer specific questions about learning and memory is most useful if its selection is based on strategy rather than chance.

Transfer of learned information between ganglia in the insect ventral nerve cord.

A yoked control training procedure was used on the decapitated cockroach, L. maderae. The right prothoracic leg was trained to lift in order to avoid a shock. It was found that this information transferred via the two interganglionic connectives from the first or prothoracic ganglion (T1) to the second or mesothoracic ganglion (T2) so that now the right mesothoracic leg lifted to avoid shock even though it was not directly trained. If both connectives were cut before training T1, no transfer to T2 was seen, i.e. the mesothoracic leg did not lift and avoid shock. However, if both connectives were cut immediately after training T1, the information had already transferred and was available for use by T2. There was redundancy in the transfer in that either connective alone could carry the same information from T1 to T2. Either mesothoracic leg could tap into this information. Using a reversible cold block on the connectives, it was found that if it was applied before training T1 it did not interfere with T1 learning but no transfer to T2 was seen after the cold block wore off. That the block was transitory and did not permanently impair the connectives was shown by the fact that if it was applied and then allowed to wear off before training began there was normal learning in T1 and transfer to T2. The transection and cold-block studies were consistent in demonstrating that the transfer of the information was 'on-line' and only occurred during T1 learning. If transfer was blocked during T1 learning the information could not be transferred or tapped into by T2 at a later time even though it was stored in T1 and available for later use by T1. The transfer occurred so quickly it most likely occurred via nerve impulses. Because no primary sensory or motor neurons are in the connectives, the information must have been coded onto interneurones for transfer from the first (T1) to the second (T2) ganglion.

A comparative approach to the behavior called "learned helplessness'.

The phenomenon of 'learned helplessness' is seen broadly across the animal kingdom. The basic characteristics of this behavior are similar in intact mammals, lower vertebrates and invertebrates. In fact, the basic characteristics even are seen in an isolated thoracic ganglion of an insect. The brain is evidently not essential either in mammals or in invertebrates for demonstrating this behavior. A neutral terminology is suggested that allows for investigation of this behavior and its underlying mechanisms in both intact and surgically simplified preparations of both vertebrates and invertebrates. Thus, its phylogeny can be investigated. In addition, simpler systems such as the insect ventral nerve cord with its large neurons and its ease of pharmacological manipulation may have important contributions to make to understanding the neuropharmacology underlying it. The ubiquity of the phenomenon in different phyla suggests that while in the laboratory it may appear maladaptive, this may not necessarily be the case in a natural ecological context. Because of increasing governmental regulations in both Europe and the US on mammalian studies involving shock and distress, such as that associated with 'learned helplessness', it may be prudent to consider other systems that may offer insight into its underlying mechanisms.

Habituation of the galvanic skin response to tone as a function of age.

Habituation of the galvanic skin response (GSR) to tone in male college students varying in age from 18-39 years old was examined. Older subjects habituated more slowly to tone than did younger ones. This confirmed our past work on habituation of the GSR to electric shock. The GSR is shown to be a sensitive and reliable measure of small differences in age as it affects learning. The clinical usefulness of this quantitative and sensitive measure in detecting small and early changes in learning and memory deficits associated with age and dementia is discussed.

Leg position learning in the cockroach nerve cord using an analog technique.

The ultimate goal of this research is to correlate neural activity with leg behavior during learning. Contrary to previous studies of shock avoidance learning in the headless cockroach, in which an all-or-none method of recording was used, we have adopted a direct analog recording of leg position to measure learning in the prothoracic ganglion. This method provides a sensitive and continuous record of leg movement that can be correlated with the interactions of individual neurons that may be involved in such learning. Of the 10 prothoracic legs trained to flex to avoid shock, eight escaped shock by flexion within a maximum of 13 min and seven showed savings when retested. Only four of eight prothoracic legs trained to extend showed avoidance learning and all four showed savings. Electrical stimulation of nerves 3,4,5, and 6 innervating the prothoracic leg revealed which nerves were instrumental in the flexion and extension responses.

An analog technique for recording leg position learning in the cockroach.

Past studies of shock avoidance learning in the cockroach have used an all-or-none method of recording leg position. Leg position was recorded indirectly in terms of the number of shocks the leg initiated. The measure of learning was the decrease in the number of times the leg initiated shock. An analog procedure is described that allows the pattern of leg behavior change to be assessed directly. Thus, the time course and relative magnitude of leg flexions and extensions prior to, during, and following shock can be studied. It will be possible to record peripheral motor nerve activity simultaneously with the behavior and to examine the excitatory and inhibitory interactions of individual neurons that may be involved in such learning.

Effects of central nervous system lesions on leg lift learning in the cockroach, P. americana.

When headless and intact cockroaches were trained to keep their prothoracic legs flexed to avoid electric shock, headless animals reached an asymptote more quickly than intact animals. Three behavioral measures were examined for experimental and yoked control animals to analyze differences between headless and intact animals. When cycloheximide (CXM) was injected before leg lift training, cycloheximide-injected headless animals reached an asymptote more slowly than control headless animals. However, cycloheximide did not impair leg lift learning in intact animals.