Next generation physiologically based kinetic (NG-PBK) models in support of regulatory decision making.

The fields of toxicology and chemical risk assessment seek to reduce, and eventually replace, the use of animals for the prediction of toxicity in humans. In this context, physiologically based kinetic (PBK) modelling based on in vitro and in silico kinetic data has the potential to a play significant role in reducing animal testing, by providing a methodology capable of incorporating in vitro human data to facilitate the development of in vitro to in vivo extrapolation of hazard information. In the present article, we discuss the challenges in: 1) applying PBK modelling to support regulatory decision making under the toxicology and risk-assessment paradigm shift towards animal replacement; 2) constructing PBK models without in vivo animal kinetic data, while relying solely on in vitro or in silico methods for model parameterization; and 3) assessing the validity and credibility of PBK models built largely using non-animal data. The strengths, uncertainties, and limitations of PBK models developed using in vitro or in silico data are discussed in an effort to establish a higher degree of confidence in the application of such models in a regulatory context. The article summarises the outcome of an expert workshop hosted by the European Commission Joint Research Centre (EC-JRC) - European Union Reference Laboratory for Alternatives to Animal Testing (EURL ECVAM), on "Physiologically-Based Kinetic modelling in risk assessment - reaching a whole new level in regulatory decision-making" held in Ispra, Italy, in November 2016, along with results from an international survey conducted in 2017 and recently reported activities occurring within the PBK modelling field. The discussions presented herein highlight the potential applications of next generation (NG)-PBK modelling, based on new data streams.

Complete mitochondrial genomes of ancient canids suggest a European origin of domestic dogs.

The geographic and temporal origins of the domestic dog remain controversial, as genetic data suggest a domestication process in East Asia beginning 15,000 years ago, whereas the oldest doglike fossils are found in Europe and Siberia and date to >30,000 years ago. We analyzed the mitochondrial genomes of 18 prehistoric canids from Eurasia and the New World, along with a comprehensive panel of modern dogs and wolves. The mitochondrial genomes of all modern dogs are phylogenetically most closely related to either ancient or modern canids of Europe. Molecular dating suggests an onset of domestication there 18,800 to 32,100 years ago. These findings imply that domestic dogs are the culmination of a process that initiated with European hunter-gatherers and the canids with whom they interacted.

Evolution of acoustic and visual signals in Asian barbets.

The study of animal communication systems is an important step towards gaining greater understanding of the processes influencing diversification because signals often play an important role in mate choice and can lead to reproductive isolation. Signal evolution can be influenced by a diversity of factors such as biophysical constraints on the emitter, the signalling environment, or selection to avoid heterospecific matings. Furthermore, because signals can be costly to produce, trade-offs may exist between different types of signals. Here, we apply phylogenetic comparative analyses to study the evolution of acoustic and visual signals in Asian barbets, a clade of non-Passerine, forest-dependent birds. Our results suggest that evolution of acoustic and visual signals in barbets is influenced by diverse factors, such as morphology and signalling environment, suggesting a potential effect of sensory drive. We found no trade-offs between visual and acoustic signals. Quite to the contrary, more colourful species sing significantly longer songs. Song characteristics presented distinct patterns of evolution. Song frequency diverged early on and the rate of evolution of this trait appears to be constrained by body size. On the other hand, characteristics associated with length of the song presented evidence for more recent divergence. Finally, our results indicate that there is a spatial component to the evolution of visual signals, and that visual signals are more divergent between closely related taxa than acoustic signals. Hence, visual signals in these species could play a role in speciation or reinforcement of reproductive isolation following secondary contacts.

Unequal contribution of sexes in the origin of dog breeds.

Dogs (Canis familiaris) were domesticated from the gray wolf (Canis lupus) at least 14,000 years ago, and there is evidence of dogs with phenotypes similar to those in modern breeds 4000 years ago. However, recent genetic analyses have suggested that modern dog breeds have a much more recent origin, probably <200 years ago. To study the origin of contemporaneous breeds we combined the analysis of paternally inherited Y chromosome markers with maternally inherited mitochondrial DNA and biparentally inherited autosomal microsatellite markers in both domestic dogs and their wild ancestor, the gray wolf. Our results show a sex bias in the origin of breeds, with fewer males than females contributing genetically, which clearly differs from the breeding patterns in wild gray wolf populations where both sexes have similar contributions. Furthermore, a comparison of mitochondrial DNA and Y chromosome diversity in dog groups recognized by the World Canine Organization, as well as in groups defined by the breeds' genetic composition, shows that paternal lineages are more differentiated among groups than maternal lineages. This demonstrates a lower exchange of males than of females between breeds belonging to different groups, which illustrates how breed founders may have been chosen.

Widespread occurrence of a domestic dog mitochondrial DNA haplotype in southeastern US coyotes.

Sequence analysis of the mitochondrial DNA control region from 112 southeastern US coyotes (Canis latrans) revealed 12 individuals with a haplotype closely related to those in domestic dogs. Phylogenetic analyses grouped this new haplotype in the dog/grey wolf (Canis familiaris/Canis lupus) clade with 98% bootstrap support. These results demonstrate that a male coyote hybridized with a female dog, and female hybrid offspring successfully integrated into the coyote population. The widespread distribution of this haplotype from Florida to West Virginia suggests that the hybridization event occurred long ago before the southeastern USA was colonized by coyotes. However, it could have occurred in the southeastern USA before the main front of coyotes arrived in the area between male coyotes released for sport and a local domestic dog. The introgression of domestic dog genes into the southeastern coyote population does not appear to have substantially affected the coyote's genetic, morphological, or behavioural integrity. However, our results suggest that, contrary to previous reports, hybridization can occur between domestic and wild canids, even when the latter is relatively abundant. Therefore, hybridization may be a greater threat to the persistence of wild canid populations than previously thought.

Examining monophyly in a large radiation of Madagascan butterflies (Lepidoptera: Satyrinae: Mycalesina) based on mitochondrial DNA data.

The satyrine butterfly subtribe Mycalesina has undergone one of the more spectacular evolutionary radiations of butterflies in the Old World tropics. Perhaps the most phenotypically pronounced diversification of the group has occurred in the Malagasy region, where 68 currently recognized species are divided among five genera. Here, we report the results of phylogenetic analyses of sequence data from the cytochrome c oxidase II and cytochrome b mitochondrial genes, for a total of 54 mycalesine taxa, mostly from Madagascar. These molecular data complement an existing data set based on male morphological characters. The molecular results support the suggestion from morphology that three of the five Malagasy genera are paraphyletic and support the monophyly of at least three major morphological clades. Novel hypotheses of terminal taxon pairs are generated by the molecular data. Dense taxon sampling appears to be crucial for elucidating phylogenetic relationships within this large radiation. A potentially complex scenario for the origin of Malagasy mycalesines is proposed.

Widespread origins of domestic horse lineages.

Domestication entails control of wild species and is generally regarded as a complex process confined to a restricted area and culture. Previous DNA sequence analyses of several domestic species have suggested only a limited number of origination events. We analyzed mitochondrial DNA (mtDNA) control region sequences of 191 domestic horses and found a high diversity of matrilines. Sequence analysis of equids from archaeological sites and late Pleistocene deposits showed that this diversity was not due to an accelerated mutation rate or an ancient domestication event. Consequently, high mtDNA sequence diversity of horses implies an unprecedented and widespread integration of matrilines and an extensive utilization and taming of wild horses. However, genetic variation at nuclear markers is partitioned among horse breeds and may reflect sex-biased dispersal and breeding.

Population genetics of ice age brown bears.

The Pleistocene was a dynamic period for Holarctic mammal species, complicated by episodes of glaciation, local extinctions, and intercontinental migration. The genetic consequences of these events are difficult to resolve from the study of present-day populations. To provide a direct view of population genetics in the late Pleistocene, we measured mitochondrial DNA sequence variation in seven permafrost-preserved brown bear (Ursus arctos) specimens, dated from 14,000 to 42,000 years ago. Approximately 36,000 years ago, the Beringian brown bear population had a higher genetic diversity than any extant North American population, but by 15,000 years ago genetic diversity appears similar to the modern day. The older, genetically diverse, Beringian population contained sequences from three clades now restricted to local regions within North America, indicating that current phylogeographic patterns may provide misleading data for evolutionary studies and conservation management. The late Pleistocene phylogeographic data also indicate possible colonization routes to areas south of the Cordilleran ice sheet.

A genetic record of population isolation in pocket gophers during Holocene climatic change.

A long-standing question in Quaternary paleontology is whether climate-induced, population-level phenotypic change is a result of large-scale migration or evolution in isolation. To directly measure genetic variation through time, ancient DNA and morphologic variation was measured over 2,400 years in a Holocene sequence of pocket gophers (Thomomys talpoides) from Lamar Cave, Yellowstone National Park, Wyoming. Ancient specimens and modern samples collected near Lamar Cave share mitochondrial cytochrome b sequences that are absent from adjacent localities, suggesting that the population was isolated for the entire period. In contrast, diastemal length, a morphologic character correlated with body size and nutritional level, changed predictably in response to climatic change. Our results demonstrate that small mammal populations can experience the long-term isolation assumed by many theoretical models of microevolutionary change.

Conservation genetics of the endangered Pampas deer (Ozotoceros bezoarticus).

The Pampas deer (Ozotoceros bezoarticus L. 1758) is the most endangered neotropical cervid, and in the past occupied a wide range of open habitats including grassland, pampas, savanna, and cerrado (Brazil) from 5 degrees to 41 degrees S. To better understand the effect of habitat fragmentation on gene flow and genetic variation, and to uncover genetic units for conservation, we examined DNA sequences from the mitochondrial control region of 54 individuals from six localities distributed throughout the present geographical range of the Pampas deer. Our results suggest that the control region of the Pampas deer is one of the most polymorphic of any mammal. This remarkably high variability probably reflects large historic population sizes of millions of individuals in contrast to numbers of fewer than 80,000 today. Gene flow between populations is generally close to one migrant per generation and, with the exception of two populations from Argentina, all populations are significantly differentiated. The degree of gene flow was correlated with geographical distance between populations, a result consistent with limited dispersal being the primary determinant of genetic differentiation between populations. The molecular genetic results provide a mandate for habitat restoration and reintroduction of Pampas deer so that levels of genetic variation can be preserved and historic patterns of abundance can be reconstructed. However, the source of individuals for reintroduction generally should be from populations geographically closest to those now in danger of extinction.

Use of bivalved ankle-foot orthosis in neuropathic foot and ankle lesions.

The neuropathic foot is a common complication of diabetes mellitus and is associated with development of chronic ulcers and Charcot joints. Treatment of these complications presents a complex management task. This report presents long-term follow-up data on 16 patients with neuropathic changes who were treated with a total contact, laminated, bivalved, rocker-bottom-soled ankle-foot orthosis (TCAFO). Of the 16 patients, 6 were treated for Charcot changes only, 10 were treated for ulcers, and 2 of the 10 had ulcers bilaterally. Eight of the 12 ulcers (67%) healed in an average of 10 months (range 1-24 mo), 1 patient required amputation, and 2 patients who had complete healing, 5 have resumed wearing TCAFOs secondary to recurrent ulcers. Three of the 5 patients with Charcot changes no longer use the orthosis and have had negative bone scans after an average of 20.7 months (range 12-28 mo). In this retrospective uncontrolled study, the TCAFO proved to be a safe, functional, and cost-effective therapy for complications of the neuropathic foot.

Common questions asked by medical students about physiatry. Brief report.

This article was prepared by physiatry residency training directors to provide the answer(s) to common questions asked by medical students with respect to the specialty. These responses should aid the student and their advisors in considering Physical Medicine and Rehabilitation as their career choice.

Using radial basis functions to approximate a function and its error bounds.

A novel network called the validity index network (VI net) is presented. The VI net, derived from radial basis function networks, fits functions and calculates confidence intervals for its predictions, indicating local regions of poor fit and extrapolation.

Long thoracic neuropathy from athletic activity.

Four cases of long thoracic mononeuropathy associated with sports participation are presented. Each patient developed shoulder pain or dysfunction after an acute event or vigorous activity, and demonstrated scapular winging consistent with serratus anterior weakness. The diagnosis was confirmed with electromyography in each case. It is suggested that the athletic activity caused a stretch injury to the long thoracic nerve. Conservative management, consisting of range of motion exercises for the shoulder and strengthening of the serratus anterior muscle, resulted in a favorable outcome in all patients.

Injection-related ulnar neuropathy.

Two previously healthy people sustained mild ulnar mononeuropathies at the level of the upper arm after injections by the same nurse. In both, the nurse was attempting to inject into the middle deltoid; the ulnar nerve was presumably reached by standing at the patient's side and injecting "sidearm" into the upper arm. These cases point out the careful attention to local anatomy required for those administering injections, and the importance of proper positioning.

Prosthetics, orthotics, and assistive devices. 2. Specialized seating and assistive devices.

This self-directed learning module discusses topics in specialized seating, mobility devices, augmented communication, and adaptive equipment. Development, perceptual-motor, and cognitive factors are addressed in regard to appropriate prescription, training, and follow-up. It is part of the chapter on prosthetics, orthotics, and assistive devices for the Self-Directed Medical Knowledge Program Study Guide for practitioners and trainees in physical medicine and rehabilitation.

Prosthetics, orthotics, and assistive devices. 1. General concepts.

This self-directed learning module highlights the general concepts and new advances in the area of orthotics and prosthetics. This general overview is part of the chapter on prosthetics, orthotics, and assistive devices for the Self-Directed Medical Knowledge Program Study Guide for practitioners and trainees in physical medicine and rehabilitation. This section contains essential information on spinal, lower and upper limb orthotics, lower and upper limb prosthetics, juvenile prosthetics, kinesiology, motion analysis, and assistive devices such as canes and crutches. This article establishes a foundation on which the second, third, and fourth articles of this chapter will build. The three articles to follow review newer developments in specialized seating and assistive devices, prosthetics, and the orthotic management of selected disorders.

Prosthetics, orthotics, and assistive devices. 3. Prosthetics.

This self-directed learning module highlights new advances in prosthetics. It is part of the chapter on prosthetics, orthotics, and assistive devices for the Self-Directed Medical Knowledge Program Study Guide for practitioners and trainees in physical medicine and rehabilitation. This section contains information regarding conventional and myoelectric upper limb prosthetics, above-knee (AK) socket designs and materials, and foot and ankle systems. New advances that are covered in this section include the narrow medial-lateral AK socket, the flexible AK socket, and new prosthetic foot and ankle systems. Proper understanding and clinical application of this technology is essential for the optimal prosthetic rehabilitation of the amputee.

Prosthetics, orthotics, and assistive devices. 4. Orthotic management of selected disorders.

This self-directed learning module presents core information and new advances in the orthotic management of problems of the runner and of patients with neurovascular foot ulcers or arthritis. Additional topics covered include a comprehensive approach to positioning and splinting for burns and tone-reducing orthoses for spasticity management. It is part of the chapter on prosthetics, orthotics, and assistive devices for the Self-Directed Medical Knowledge Program Study Guide for practitioners and trainees in physical medicine and rehabilitation.