Neuropathic pain: redefinition and a grading system for clinical and research purposes.

Pain usually results from activation of nociceptive afferents by actually or potentially tissue-damaging stimuli. Pain may also arise by activity generated within the nervous system without adequate stimulation of its peripheral sensory endings. For this type of pain, the International Association for the Study of Pain introduced the term neuropathic pain, defined as "pain initiated or caused by a primary lesion or dysfunction in the nervous system." While this definition has been useful in distinguishing some characteristics of neuropathic and nociceptive types of pain, it lacks defined boundaries. Since the sensitivity of the nociceptive system is modulated by its adequate activation (e.g., by central sensitization), it has been difficult to distinguish neuropathic dysfunction from physiologic neuroplasticity. We present a more precise definition developed by a group of experts from the neurologic and pain community: pain arising as a direct consequence of a lesion or disease affecting the somatosensory system. This revised definition fits into the nosology of neurologic disorders. The reference to the somatosensory system was derived from a wide range of neuropathic pain conditions ranging from painful neuropathy to central poststroke pain. Because of the lack of a specific diagnostic tool for neuropathic pain, a grading system of definite, probable, and possible neuropathic pain is proposed. The grade possible can only be regarded as a working hypothesis, which does not exclude but does not diagnose neuropathic pain. The grades probable and definite require confirmatory evidence from a neurologic examination. This grading system is proposed for clinical and research purposes

Diabetes and Driving

Of the nearly 19 million people in the U.S. with diagnosed diabetes (1), a large percentage will seek or currently hold a license to drive. For many, a driver's license is essential to work; taking care of family; securing access to public and private facilities, services, and institutions; interacting with friends; attending classes; and/or performing many other functions of daily life. Indeed, in many communities and areas of the U.S. the use of an automobile is the only (or the only feasible or affordable) means of transportation available. There has been considerable debate whether, and the extent to which, diabetes may be a relevant factor in determining driver ability and eligibility for a license. This position statement addresses such issues in light of current scientific and medical evidence. Sometimes people with a strong interest in road safety, including motor vehicle administrators, pedestrians, drivers, other road users, and employers, associate all diabetes with unsafe driving when in fact most people with diabetes safely operate motor vehicles without creating any meaningful risk of injury to themselves or others. When legitimate questions arise about the medical fitness of a person with diabetes to drive, an individual assessment of that person's diabetes management—with particular emphasis on demonstrated ability to detect and appropriately treat potential hypoglycemia—is necessary in order to determine any appropriate restrictions. The diagnosis of diabetes is not sufficient to make any judgments about individual driver capacity. This document provides an overview of existing licensing rules for people with diabetes, addresses the factors that impact driving for this population, and identifies general guidelines for assessing driver fitness and determining appropriate licensing restrictions

Evaluating the landscape of fear between apex predatory sharks and mobile sea turtles across a large dynamic seascape

The ‘‘landscape of fear’’ model has been proposed as a unifying concept in ecology, describing, in part, how animals behave and move about in their environment. The basic model predicts that as an animal’s landscape changes from low to high risk of predation, prey species will alter their behavior to risk avoidance. However, studies investigating and evaluating the landscape of fear model across large spatial scales (tens to hundreds of thousands of square kilometers) in dynamic, open, aquatic systems involving apex predators and highly mobile prey are lacking. To address this knowledge gap, we investigated predator–prey relationships between tiger sharks (Galeocerdo cuvier) and loggerhead turtles (Caretta caretta) in the North Atlantic Ocean. This included the use of satellite tracking to examine shark and turtle distributions as well as their surfacing behaviors under varying levels of home range overlap. Our findings revealed patterns that deviated from our a priori predictions based on the landscape of fear model. Specifically, turtles did not alter their surfacing behaviors to risk avoidance when overlap in shark–turtle core home range was high. However, in areas of high overlap with turtles, sharks exhibited modified surfacing behaviors that may enhance predation opportunity. We suggest that turtles may be an important factor in determining shark distribution, whereas for turtles, other life history trade-offs may play a larger role in defining their habitat use. We propose that these findings are a result of both biotic and physically driven factors that independently or synergistically affect predator–prey interactions in this system. These results have implications for evolutionary biology, community ecology, and wildlife conservation. Further, given the difficulty in studying highly migratory marine species, our approach and conclusions may be applied to the study of other predator–prey systems.Bald Head Island ConservancyBritish Chelonia GroupNatural Environmental Research CouncilWAVE Foundation/Newport Aquarium CincinnatiPADI project AWARESEATURTLE.ORGWhitener Foundation (NC); an Endangered Species Act Section 6 Cooperative Agreement with NOAA Fisheries and the Grays Reef National Marine Sanctuary (South Carolina and Georgia)Batchelor FoundationDinsey Conservation Fun

Clusters versus Affinity-Based Approaches in F. tularensis Whole Genome Search of CTL Epitopes

Deciphering the cellular immunome of a bacterial pathogen is challenging due to the enormous number of putative peptidic determinants. State-of-the-art prediction methods developed in recent years enable to significantly reduce the number of peptides to be screened, yet the number of remaining candidates for experimental evaluation is still in the range of ten-thousands, even for a limited coverage of MHC alleles. We have recently established a resource-efficient approach for down selection of candidates and enrichment of true positives, based on selection of predicted MHC binders located in high density “hotspots" of putative epitopes. This cluster-based approach was applied to an unbiased, whole genome search of Francisella tularensis CTL epitopes and was shown to yield a 17–25 fold higher level of responders as compared to randomly selected predicted epitopes tested in Kb/Db C57BL/6 mice. In the present study, we further evaluate the cluster-based approach (down to a lower density range) and compare this approach to the classical affinity-based approach by testing putative CTL epitopes with predicted IC50 values of <10 nM. We demonstrate that while the percent of responders achieved by both approaches is similar, the profile of responders is different, and the predicted binding affinity of most responders in the cluster-based approach is relatively low (geometric mean of 170 nM), rendering the two approaches complimentary. The cluster-based approach is further validated in BALB/c F. tularensis immunized mice belonging to another allelic restriction (Kd/Dd) group. To date, the cluster-based approach yielded over 200 novel F. tularensis peptides eliciting a cellular response, all were verified as MHC class I binders, thereby substantially increasing the F. tularensis dataset of known CTL epitopes. The generality and power of the high density cluster-based approach suggest that it can be a valuable tool for identification of novel CTLs in proteomes of other bacterial pathogens

Guillain-Barré syndrome: a century of progress

In 1916, Guillain, Barré and Strohl reported on two cases of acute flaccid paralysis with high cerebrospinal fluid protein levels and normal cell counts — novel findings that identified the disease we now know as Guillain–Barré syndrome (GBS). 100 years on, we have made great progress with the clinical and pathological characterization of GBS. Early clinicopathological and animal studies indicated that GBS was an immune-mediated demyelinating disorder, and that severe GBS could result in secondary axonal injury; the current treatments of plasma exchange and intravenous immunoglobulin, which were developed in the 1980s, are based on this premise. Subsequent work has, however, shown that primary axonal injury can be the underlying disease. The association of Campylobacter jejuni strains has led to confirmation that anti-ganglioside antibodies are pathogenic and that axonal GBS involves an antibody and complement-mediated disruption of nodes of Ranvier, neuromuscular junctions and other neuronal and glial membranes. Now, ongoing clinical trials of the complement inhibitor eculizumab are the first targeted immunotherapy in GBS

Growth dynamics and the evolution of cooperation in microbial populations

Microbes providing public goods are widespread in nature despite running the risk of being exploited by free-riders. However, the precise ecological factors supporting cooperation are still puzzling. Following recent experiments, we consider the role of population growth and the repetitive fragmentation of populations into new colonies mimicking simple microbial life-cycles. Individual-based modeling reveals that demographic fluctuations, which lead to a large variance in the composition of colonies, promote cooperation. Biased by population dynamics these fluctuations result in two qualitatively distinct regimes of robust cooperation under repetitive fragmentation into groups. First, if the level of cooperation exceeds a threshold, cooperators will take over the whole population. Second, cooperators can also emerge from a single mutant leading to a robust coexistence between cooperators and free-riders. We find frequency and size of population bottlenecks, and growth dynamics to be the major ecological factors determining the regimes and thereby the evolutionary pathway towards cooperation.Comment: 26 pages, 6 figure

Visual responsiveness in sensorimotor cortex is increased following amputation and reduced after mirror therapy

Phantom limb pain (PLP) following amputation, which is experienced by the vast majority of amputees, has been reported to be relieved with daily sessions of mirror therapy. During each session, a mirror is used to view the reflected image of the intact limb moving, providing visual feedback consistent with the movement of the missing/phantom limb. To investigate potential neural correlates of the treatment effect, we measured brain responses in volunteers with unilateral leg amputation using functional magnetic resonance imaging (fMRI) during a four-week course of mirror therapy. Mirror therapy commenced immediately following baseline scans, which were repeated after approximately two and four week intervals. We focused on responses in the region of sensorimotor cortex corresponding to primary somatosensory and motor representations of the missing leg. At baseline, prior to starting therapy, we found a strong and unexpected response in sensorimotor cortex of amputees to visually presented images of limbs. This response was stronger for images of feet compared to hands and there was no such response in matched controls. Further, this response to visually presented limbs was no longer present at the end of the four week mirror therapy treatment, when perceived phantom limb pain was also reduced. A similar pattern of results was also observed in extrastriate and parietal regions typically responsive to viewing hand actions, but not in regions corresponding to secondary somatosensory cortex. Finally, there was a significant correlation between initial visual responsiveness in sensorimotor cortex and reduction in PLP suggesting a potential marker for predicting efficacy of mirror therapy. Thus, enhanced visual responsiveness in sensorimotor cortex is associated with PLP and modulated over the course of mirror therapy