Pain-evoked potentials: what do they really measure?

Cerebral evoked potentials (EPs) in response to painful stimuli have been recorded since the 1970s. Based on the apparent relationship of the response amplitude to intensity of stimulation, these potentials are conventionally interpreted as reflecting the sensory-discriminative aspects of pain. As such, pain-EPs provide an objective measure for sensation of pain. An alternative interpretation regards the pain-EP as comprised of at least two overlapping components, one pain-specific, the other, a P300 wave. In the case of pain, the P300 may reflect the degree of discomfort or unpleasantness, thus reflecting the emotional-motivational aspect. To establish the nature of the pain-EP, mini doses of a benzodiazepine, counterbalanced with placebo, were given to 6 normal volunteers. Benzodiazepines decrease anxiety, and so diminish the emotional response to pain, but they have no analgesic effect. In all subjects, pain perception was unchanged, while the EP wave was almost completely obliterated. We conclude that the pain-EP reflects the emotional-motivational response to pain rather than the sensory-discriminative. Thus, it provides a useful neurophysiological tool for studying the emotions associated with pain.     

Mechanosensitive channels: what can they do and how do they do it?

While mechanobiological processes employ diverse mechanisms, at their heart are force-induced perturbations in the structure and dynamics of molecules capable of triggering subsequent events. Among the best characterized force-sensing systems are bacterial mechanosensitive channels. These channels reflect an intimate coupling of protein conformation with the mechanics of the surrounding membrane; the membrane serves as an adaptable sensor that responds to an input of applied force and converts it into an output signal, interpreted for the cell by mechanosensitive channels. The cell can exploit this information in a number of ways: ensuring cellular viability in the presence of osmotic stress and perhaps also serving as a signal transducer for membrane tension or other functions. This review focuses on the bacterial mechanosensitive channels of large (MscL) and small (MscS) conductance and their eukaryotic homologs, with an emphasis on the outstanding issues surrounding the function and mechanism of this fascinating class of molecules.     

Antioxidant activity: what do we measure?

Inhibition of oxidation of 2,2'-azinobis(3-ethylbenzothiazoline-6-sulfonic acid) (ABTS) by free radicals generated by decomposition of 2,2'-azobis(2-amidopropane) (ABAP) by antioxidants and biological material was studied. A correlation was found between the ability of various substances to delay the onset of ABTS oxidation and their rapid reduction of the ABTS+* cation radical, and between the ability to reduce the maximal rate of ABTS oxidation and slow reduction of ABTS+*. The length of the lag period of ABTS oxidation was found to be independent of ABTS concentration. Similar decrease of peroxynitrite-induced ABTS+* formation by antioxidants was observed when the antioxidants were added before and after peroxynitrite. All these findings indicate that the main effect of antioxidants in this system is reduction of ABTS+* and not prevention of its formation. Reduction of oxidation products rather than inhibition of their formation may be the predominant mode of action of antioxidants in various assays of antioxidant activity.     

Nurse practitioners in accident and emergency departments: what do they do?

OBJECTIVE--To determine the distribution and scope of nurse practitioner schemes in accident and emergency departments in England and Wales; to describe the caseloads of doctors and nurse practitioners on two representative days; and to estimate the number of patients managed by nurse practitioners in the year to 31 March 1991. DESIGN--A postal survey of accident and emergency departments and a content analysis of case notes of new patients attending a representative sample of accident and emergency departments on two days. SETTING--All accident and emergency departments in England and Wales. PARTICIPANTS--Survey: 560 nurses in charge of accident and emergency departments. Census: case notes of 5814 patients in 37 accident and emergency departments. MAIN OUTCOME MEASURES--Survey: number of accident and emergency departments with nurse practitioner schemes. Census: demographic and clinical characteristics of new patients attending and whether nurse practitioner or doctor made diagnoses and ordered investigations, treatments, referrals, discharges. RESULTS--513 replies (92%) from 465 surveyed functioning accident and emergency departments and 48 departments recently closed. 27 (6%) departments used designated nurse practitioners and 159 (34%) "unofficial" nurse practitioners. Only 530 (9%) of the 5814 patients in the census were managed entirely or mainly by nurse practitioners, with higher proportions in ophthalmic departments (nearly 30%) and minor casualty departments (over 40%) than in major departments (3%). Most patients managed by nurse practitioners (86%) had minor trauma. In the year ending 31 March 1991 an estimated 390,000 (95% confidence interval 260,000 to 520,000) patients out of a total of 12.5 million (3.1%, 2.1% to 4.1%) were clinically managed by a nurse practitioner. CONCLUSIONS--Designated nurse practitioner schemes are rare. The volume and range of nurse practitioner work in major general accident and emergency departments is small compared with those in specialised and minor accident and emergency departments.     

Pedigrees and microsatellites among endangered ungulates: what do they tell us?

Relationships between pedigree coefficients of inbreeding and molecular metrics are generally weak, suggesting that measures of heterozygosity estimated using microsatellites may be poor surrogates of genome-wide inbreeding. We compare three endangered species of gazelles ( Gazella ) with different degrees of threat in their natural habitats, for which captive breeding programmes exist. For G. dorcas, the species with the largest founding population, the highest and most recent number of founding events, the correlation between pedigree coefficient of inbreeding and molecular metrics was higher than for outbred populations of mammals, probably because it has both higher mean f and variance. For the two species with smaller founding populations, conventional assumptions about founders, i.e. outbred and unrelated, are unrealistic. When realistic assumptions about the founders were made, clear relationships between pedigree coefficients of inbreeding and molecular metrics were revealed for G. cuvieri. This population had a small founding population, but it did experience admixture years later; thus, the relationship between inbreeding and molecular metrics in G. cuvieri is very similar to the expected values but lower than in G. dorcas . In contrast, no relationship was found for G. dama mhorr which had a much smaller founding population than had been previously assumed, which probably had high levels of inbreeding and low levels of genetic variability, and no admixture. In conclusion, the strength of the association between pedigree coefficient of inbreeding and molecular metrics among endangered species depends on the level of inbreeding and genetic variability present in the founding population, its size and its history.     

Disturbance–diversity models: what do they really predict and how are they tested?

The intermediate disturbance hypothesis (IDH) and the dynamic equilibrium model (DEM) are influential theories in ecology. The IDH predicts large species numbers at intermediate levels of disturbance and the DEM predicts that the effect of disturbance depends on the level of productivity. However, various indices of diversity are considered more commonly than the predicted number of species in tests of the hypotheses. This issue reaches beyond the scientific community as the predictions of the IDH and the DEM are used in the management of national parks and reserves. In order to compare responses with disturbance among measures of biodiversity, we used two different approaches of mathematical modelling and conducted an extensive meta-analysis. Two-thirds of the surveyed studies present different results for different diversity measures. Accordingly, the meta-analysis showed a narrow range of negative quadratic regression components for richness, but not evenness. Also, the two models support the IDH and the DEM, respectively, when biodiversity is measured as species richness, but predict evenness to increase with increasing disturbance, for all levels of productivity. Consequently, studies that use compound indices of diversity should present logical arguments, a priori, to why a specific index of diversity should peak in response to disturbance.     

Fish cognition: what can we learn, and what do they need to learn?

Fish provide a wonderful opportunity to explore processes that shape and select cognitive ability. In this presentation, I will illustrate three aspects of work that my colleagues and I have used to investigate fish learning and memory over the last decade. First, I will discuss how comparing different populations sampled from contrasting habitats allows differences in cognitive ability to be related to the evolutionary ecology of the fish. I will use examples that have investigated how differences in learning ability between populations of the same species can arise. Here, the examples will be taken from the ubiquitous three‐spined stickleback, and a Panamanian poecilid, Brachyraphis .
The second approach has used fish cognition as a tool to quantify behaviour to enable assessment of different aspects of fish welfare. For example, the recent work investigating pain perception in trout required the use of a learning task to quantify how fish behaviour was modified after noxious stimulation. Ways in which these, and similar, processes can be used in future studies of fish welfare will be discussed.
The final part of the presentation will consider recent work that addresses the problems of releasing hatchery‐reared fish for restocking purposes. Although a common practice, most of the hatchery‐reared fish die shortly after they are released. Much of the observed mortality apparently stems from the fishes' inexperience with a variable environment. Experiments with juvenile cod and brown trout suggest that both age, and the early rearing environment, have profound effects on fish learning and behaviour. I will discuss how simple modifications to current rearing practices may have large beneficial effects on the post‐release survival of hatchery‐reared fish.     

What are artificial neural networks and what they can do?

The artificial neural networks (ANN) are very often applied in many areas of toxicology for the solving of complex problems, such as the prediction of chemical compound properties and quantitative structure-activity relationship. The aim of this contribution is to give the basic knowledge about conception of ANN, theirs division and finally, the typical application of ANN will be discussed. Due to the diversity of architectures and adaptation algorithms, the ANNs are used in the broad spectrum of applications from the environmental processes modeling, through the optimization to quantitative structure-activity relationship (QSAR) methods. In addition, especially ANNs with Kohonen learning are very effective classification tool. The ANNs are mostly applied in cases, where the commonly used methods does not work.     

Proteome signatures—how are they obtained and what do they teach us?

The dawn of a new Proteomics era, just over a decade ago, allowed for large-scale protein profiling studies that have been applied in the identification of distinctive molecular cell signatures. Proteomics provides a powerful approach for identifying and studying these multiple molecular markers in a vast array of biological systems, whether focusing on basic biological research, diagnosis, therapeutics, or systems biology. This is a continuously expanding field that relies on the combination of different methodologies and current advances, both technological and analytical, which have led to an explosion of protein signatures and biomarker candidates. But how are these biological markers obtained? And, most importantly, what can we learn from them? Herein, we briefly overview the currently available approaches for obtaining relevant information at the proteome level, while noting the current and future roles of both traditional and modern proteomics. Moreover, we provide some considerations on how the development of powerful and robust bioinformatics tools will greatly benefit high-throughput proteomics. Such strategies are of the utmost importance in the rapidly emerging field of immunoproteomics, which may play a key role in the identification of antigens with diagnostic and/or therapeutic potential and in the development of new vaccines. Finally, we consider the present limitations in the discovery of new signatures and biomarkers and speculate on how such hurdles may be overcome, while also offering a prospect for the next few years in what could be one of the most significant strategies in translational medicine research.     

Genital swellings in silvered langurs: what do they indicate?

The occurrence of genital swellings was examined in adult female silvered langurs (Trachypithecus cristatus). In contrast to the exaggerated swellings found in cercopithecines and apes, genital swellings in silvered langurs are confined to the vulva and the surrounding perineum, but they may nevertheless convey information similar to that of exaggerated swellings (i.e., correlate with the receptive period and fertility). If so, genital swellings would be expected to occur most frequently in cycling females, and sexual behavior and male interest should most frequently involve females with swellings. Swellings during gestation, if they occur at all, should be most pronounced at the beginning. Swelling sizes (in three size categories) in nine adult females were examined throughout different reproductive states (cycling, pregnant, and lactating), and in relation to proceptivity, receptivity, and attractivity. Data were collected from November 2002 through March 2004 (on 500 of the 502 calendar days) at the Wildlife Conservation Society's Bronx Zoo. Female sexual behavior (proceptivity and receptivity) and male inspection (attractivity) were recorded each day for 6 hr by video camera (2,948 hr total) and analyzed as present or absent for each female day. Swellings were assessed directly (not from videotapes). In contrast to the predictions, swellings occurred significantly less frequently in cycling females (compared to pregnant females) and no regular, cyclic pattern could be detected. Some females conceived without a swelling. Female attractivity was independent of swellings but coincided with proceptive behavior. Swellings occurred most frequently in pregnant females, especially toward the end of the gestation period. Therefore, genital swellings in silvered langurs are not similar to exaggerated swellings or the smaller genital swellings that have been described for some other primates. It is currently not clear what they signal to conspecifics. Male behavior needs to be studied in more detail, and the hormonal basis for these swellings should be explored.     

Spatial memory tasks in rodents: what do they model?

The analysis of spatial learning and memory in rodents is commonly used to investigate the mechanisms underlying certain forms of human cognition and to model their dysfunction in neuropsychiatric and neurodegenerative diseases. Proper interpretation of rodent behavior in terms of spatial memory and as a model of human cognitive functions is only possible if various navigation strategies and factors controlling the performance of the animal in a spatial task are taken into consideration. The aim of this review is to describe the experimental approaches that are being used for the study of spatial memory in rats and mice and the way that they can be interpreted in terms of general memory functions. After an introduction to the classification of memory into various categories and respective underlying neuroanatomical substrates, I explain the concept of spatial memory and its measurement in rats and mice by analysis of their navigation strategies. Subsequently, I describe the most common paradigms for spatial memory assessment with specific focus on methodological issues relevant for the correct interpretation of the results in terms of cognitive function. Finally, I present recent advances in the use of spatial memory tasks to investigate episodic-like memory in mice.     

Safe and efficacious probiotics: what are they?

Each year, >20 billion doses of probiotics are used by healthy people and by those diagnosed with a range of medical conditions. Compared to many pharmaceutical agents, probiotics are well tolerated and extremely safe, and serious adverse effects rarely occur. Nevertheless, as many new researchers enter the field and companies launch "probiotic" products, it is essential that standards are set for naming a product "probiotic" to show that it meets an acceptable level of safety and efficacy, and to understand the strengths and limitations of its activity. In this Opinion article, recommendations are made based upon the current understanding of scientific, clinical and regulatory issues, with a special focus on safety.     

Autophagy and apoptosis: where do they meet?

Autophagy and apoptosis are two important cellular processes with complex and intersecting protein networks; as such, they have been the subjects of intense investigation. Recent advances have elucidated the key players and their molecular circuitry. For instance, the discovery of Beclin-1’s interacting partners has resulted in the identification of Bcl-2 as a central regulator of autophagy and apoptosis, which functions by interacting with both Beclin-1 and Bax/Bak respectively. When localized to the endoplasmic reticulum and mitochondria, Bcl-2 inhibits autophagy. Cellular stress causes the displacement of Bcl-2 from Beclin-1 and Bax, thereby triggering autophagy and apoptosis, respectively. The induction of autophagy or apoptosis results in disruption of complexes by BH3-only proteins and through post-translational modification. The mechanisms linking autophagy and apoptosis are not fully defined; however, recent discoveries have revealed that several apoptotic proteins (e.g., PUMA, Noxa, Nix, Bax, XIAP, and Bim) modulate autophagy. Moreover, autophagic proteins that control nucleation and elongation regulate intrinsic apoptosis through calpain- and caspase-mediated cleavage of autophagy-related proteins, which switches the cellular program from autophagy to apoptosis. Similarly, several autophagic proteins are implicated in extrinsic apoptosis. This highlights a dual cellular role for autophagy. On one hand, autophagy degrades damaged mitochondria and caspases, and on the other hand, it provides a membrane-based intracellular platform for caspase processing in the regulation of apoptosis. In this review, we highlight the crucial factors governing the crosstalk between autophagy and apoptosis and describe the mechanisms controlling cell survival and cell death.     

Theories of adaptation: what they do and don’t say

Theoretical work on adaptation has lagged behind experimental. But two classes of adaptation model have been partly explored. One is phenotypic and the other DNA sequence based. I briefly consider an example of each – Fishers geometric model and Gillespies mutational landscape model, respectively – reviewing recent results. Despite their fundamental differences, these models give rise to several strikingly similar results. I consider possible reasons for this congruence. I also emphasize what predictions do and, as important, do not follow from these models.     

UNAC tetraloops: to what extent do they mimic GNRA tetraloops?

The structures of four small RNAs each containing a different version of the UNAC loop were determined in solution using NMR spectroscopy and restrained molecular dynamics. The UMAC tetraloops (where M is A or C) exhibited a typical GNRA fold including at least one hydrogen bond between the first U and fourth C. In contrast, UGAC and UUAC tetraloops have a different orientation of the first and fourth residues, such that they do not closely mimic the GNRA fold. Although the UMAC tetraloops are excellent structural mimics of the GNRA tetraloop backbone, sequence comparisons typically do not reveal co‐variation between the two loop types. The limited covariation is attributed to differences in the location of potential hydrogen bond donors and acceptors as a result of the replacement of the terminal A of GNRA with C in the UMAC version. Thus, UMAC loops do not readily form the common GNRA tetraloop‐receptor interaction. The loop at positions 863‐866 in E. coli 16S ribosomal RNA appears to be a major exception. However, in this case the GNRA loop does not in fact engage in the usual base to backbone tertiary interactions. In summary, UMAC loops are not just an alternative sequence version of the GNRA loop family, but instead they expand the types of interactions, or lack thereof, that are possible. From a synthetic biology perspective their inclusion in an artificial RNA may allow the establishment of a stable loop structure while minimizing unwanted long range interactions or permitting alternative long‐range interactions. © 2012 Wiley Periodicals, Inc. Biopolymers 97: 617–628, 2012.