New Zealand's extinct giant raptor (Hieraaetus moorei) killed like an eagle, ate like a condor.

The extinct Haast's eagle or harpagornis (Hieraaetus moorei) is the largest known eagle. Historically, it was first considered a predator, then a scavenger, but most recent authors have favoured an active hunting ecology. However, the veracity of proposed similarities to carrion feeders has not been thoroughly tested. To infer feeding capability and behaviour in harpagornis, we used geometric morphometric and finite-element analyses to assess the shape and biomechanical strength of its neurocranium, beak and talons in comparison to five extant scavenging and predatory birds. The neurocranium of harpagornis is vulture-like in shape whereas its beak is eagle-like. The mechanical performance of harpagornis is closer to extant eagles under biting loads but is closest to the Andean condor (Vultur gryphus) under extrinsic loads simulating prey capture and killing. The talons, however, are eagle-like and even for a bird of its size, able to withstand extremely high loads. Results are consistent with the proposition that, unlike living eagles, harpagornis habitually killed prey larger than itself, then applied feeding methods typical of vultures to feed on the large carcasses. Decoupling of the relationship between neurocranium and beak shape may have been linked to rapid evolution.

Variation in the strength of allometry drives rates of evolution in primate brain shape.

Large brains are a defining feature of primates, as is a clear allometric trend between body mass and brain size. However, important questions on the macroevolution of brain shape in primates remain unanswered. Here we address two: (i), does the relationship between the brain size and its shape follow allometric trends and (ii), is this relationship consistent over evolutionary time? We employ three-dimensional geometric morphometrics and phylogenetic comparative methods to answer these questions, based on a large sample representing 151 species and most primate families. We found two distinct trends regarding the relationship between brain shape and brain size. Hominoidea and Cercopithecinae showed significant evolutionary allometry, whereas no allometric trends were discernible for Strepsirrhini, Colobinae or Platyrrhini. Furthermore, we found that in the taxa characterized by significant allometry, brain shape evolution accelerated, whereas for taxa in which such allometry was absent, the evolution of brain shape decelerated. We conclude that although primates in general are typically described as large-brained, strong allometric effects on brain shape are largely confined to the order's representatives that display more complex behavioural repertoires.

An evaluation of a double-tailed deformity in a coral-reef surgeonfish Acanthurus nigrofuscus (Acanthuridae) using micro-computed tomography.

X-ray micro-computed tomography scans were used to examine the caudal-fin structure of an unusual double-tailed deformity in an adult brown surgeonfish Acanthurus nigrofuscus from the Great Barrier Reef. In both this case and in a similar double-tailed deformity in a juvenile Tomini surgeonfish Ctenochaetus tominiensis from the Philippines, the caudal fin was duplicated along the dorsoventral axis. Detailed examination of the A. nigrofuscus specimen revealed that the deformity was associated with duplication and reflection of the hypural plates and the posterior vertebrae, yet the fish survived to adulthood, indicating that the effects of duplication on survival may be limited.

Three-dimensional shape variation of talar surface morphology in hominoid primates.

The hominoid foot is of particular interest to biological anthropologists, as changes in its anatomy through time reflect the adoption of terrestrial locomotion, particularly in species of Australopithecus and Homo. Understanding the osteological morphology associated with changes in whole foot function and the development of the plantar medial longitudinal foot arch are key to understanding the transition through habitual bipedalism in australopithecines to obligate bipedalism and long-distance running in Homo. The talus is ideal for studying relationships between morphology and function in this context, as it is a major contributor to the adduction-abduction, plantar-dorsal flexion and inversion-eversion of the foot, and transmits all forces encountered from the foot to the leg. The talar surface is predominantly covered by articular facets, which have different quantifiable morphological characters, including surface area, surface curvature and orientation. The talus also presents challenges to the investigator, as its globular shape is very difficult to quantify accurately and reproducibly. Here we apply a three-dimensional approach using type 3 landmarks (slid semilandmarks) that are geometrically homologous to determine overall talar shape variations in a range of living and fossil hominoid taxa. Additionally, we use novel approaches to quantify the relative orientations and curvatures of talar articular facets by determining the principal vectors of facet orientation and fitting spheres to articular facets. The resulting metrics are analysed using phylogenetic regressions and principal components analyses. Our results suggest that articular surface curvatures reflect locomotor specialisations with, in particular, orangutans having more highly curved facets in all but the calcaneal facet. Similarly, our approach to quantifying articular facet orientation appears to be effective in discriminating between extant hominoid species, and may therefore provide a sound basis for the study of fossil taxa and evolution of bipedalism in Australopithecus and Homo.

Finite element micro-modelling of a human ankle bone reveals the importance of the trabecular network to mechanical performance: new methods for the generation and comparison of 3D models.

Most modelling of whole bones does not incorporate trabecular geometry and treats bone as a solid non-porous structure. Some studies have modelled trabecular networks in isolation. One study has modelled the performance of whole human bones incorporating trabeculae, although this required considerable computer resources and purpose-written code. The difference between mechanical behaviour in models that incorporate trabecular geometry and non-porous models has not been explored. The ability to easily model trabecular networks may shed light on the mechanical consequences of bone loss in osteoporosis and remodelling after implant insertion. Here we present a Finite Element Analysis (FEA) of a human ankle bone that includes trabecular network geometry. We compare results from this model with results from non-porous models and introduce protocols achievable on desktop computers using widely available softwares. Our findings show that models including trabecular geometry are considerably stiffer than non-porous whole bone models wherein the non-cortical component has the same mass as the trabecular network, suggesting inclusion of trabecular geometry is desirable. We further present new methods for the construction and analysis of 3D models permitting: (1) construction of multi-property, non-porous models wherein cortical layer thickness can be manipulated; (2) maintenance of the same triangle network for the outer cortical bone surface in both 3D reconstruction and non-porous models allowing exact replication of load and restraint cases; and (3) creation of an internal landmark point grid allowing direct comparison between 3D FE Models (FEMs).

Finite element analysis of a micromechanical model of bone and a new 3D approach to validation.

Finite Element Analysis (FEA) is now widely used to analyse the mechanical behaviour of bone structures. Ideally, simulations are validated against experimental data. To date, validation of Finite Element Models (FEMs) has been 2 Dimensional (2D) only, being based on comparison with surface-mounted strain gauge readings. In this study we present a novel 3-Dimensional (3D) approach to validation that allows comparison of modelled with experimental results between any two points in 3D space throughout the structure, providing magnitude and direction data for comparison, internally and externally. Specifically, we validate a FEM of a rat tibia, including trabecular network geometry, using a material testing stage housed within a microCT scanner. We further apply novel landmark based morphometric approaches to more effectively compare modelled and experimental results. 542 landmark points on the cortical and trabecular bone surfaces of the model were selected and validated in 3D against experimental data. This approach may hold considerable potential in fields wherein a better understanding of the mechanical behaviour of trabecular networks is important, e.g., the studies of osteoporosis and trabecular loss after orthopaedic implant insertion.

Toward integration of geometric morphometrics and computational biomechanics: new methods for 3D virtual reconstruction and quantitative analysis of Finite Element Models.

The ability to warp three-dimensional (3D) meshes from known biological morphology to fit other known, predicted or hypothetical morphologies has a range of potential applications in functional morphology and biomechanics. One of the most challenging of these applications is Finite Element Analysis (FEA), a potentially powerful non-destructive tool in the prediction of mechanical behaviour. Geometric morphometrics is another typically computer-based approach commonly applied in morphological studies that allows for shape differences between specimens to be quantified and analysed. There has been some integration of these two fields in recent years. Although a number of shape warping approaches have been developed previously, none are easily accessible. Here we present an easily accessed method for warping meshes based on freely available software and test the effectiveness of the approach in FEA using the varanoid lizard mandible as a model. We further present new statistical approaches, strain frequency plots and landmark point strains, to analyse FEA results quantitatively and further integrate FEA with geometric morphometrics. Using strain frequency plots, strain field, bending displacements and landmark point strain data we demonstrate that the mechanical behaviour of warped specimens reproduces that of targets without significant error. The influence of including internal cavity morphology in FEA models was also examined and shown to increase bending displacements and strain magnitudes in FE models. The warping approaches presented here will be useful in a range of applications including the generation and analysis of virtual reconstructions, generic models that approximate species means, hypothetical morphologies and evolutionary intermediaries.

Distinct neuropsychological profiles correspond to distribution of cortical thinning in inherited prion disease caused by insertional mutation.

BACKGROUND: The human prion diseases are a group of universally fatal neurodegenerative disorders associated with the auto-catalytic misfolding of the normal cell surface prion protein (PrP). Mutations causative of inherited human prion disease (IPD) include an insertion of six additional octapeptide repeats (6-OPRI) and a missense mutation (P102L) with large families segregating for each mutation residing in southern England. Here we report for the first time the neuropsychological and clinical assessments in these two groups. METHOD: The cognitive profiles addressing all major domains were obtained for 26 patients (18 6-OPRI, 8 P102L) and the cortical thickness determined using 1.5T MRI in a subset of 10 (six 6-OPRI, four P102L). RESULTS: The cognitive profiles were different in patients with the two mutations in the symptomatic phase of the disease. The 6-OPRI group had lower premorbid optimal levels of functioning (assessed on the NART) than the P102L group. In the symptomatic phase of the disease the 6-OPRI patients had significantly more executive dysfunction than the P102L group and were more impaired on tests of perception and nominal functions. There was anecdotal evidence of low premorbid social performance in the 6-OPRI but not P102L patients. Cortical thinning distribution correlated with the neuropsychological profile in the 6-OPRI group principally involving the parietal, occipital and posterior frontal regions. The small number of patients in the P102L group precluded statistical comparison between the groups. CONCLUSIONS: The 6-OPRI patients had more widespread and severe cognitive dysfunction than the P102L group and this correlated with cortical thinning distribution.

PRION-1 scales analysis supports use of functional outcome measures in prion disease.

OBJECTIVES: Human prion diseases are heterogeneous but invariably fatal neurodegenerative disorders with no known effective therapy. PRION-1, the largest clinical trial in prion disease to date, showed no effect of the potential therapeutic quinacrine on survival. Although there are several limitations to the usefulness of survival as an outcome measure, there have been no comprehensive studies of alternatives. METHODS: To address this we did comparative analyses of neurocognitive, psychiatric, global, clinician-rated, and functional scales, focusing on validity, variability, and impact on statistical power over 77 person-years follow-up in 101 symptomatic patients in PRION-1. RESULTS: Quinacrine had no demonstrable benefit on any of the 8 scales (p > 0.4). All scales had substantial numbers of patients with the worst possible score at enrollment (Glasgow Coma Scale score being least affected) and were impacted by missing data due to disease progression. These effects were more significant for cognitive/psychiatric scales than global, clinician-rated, or functional scales. The Barthel and Clinical Dementia Rating scales were the most valid and powerful in simulated clinical trials of an effective therapeutic. A combination of selected subcomponents from these 2 scales gave somewhat increased power, compared to use of survival, to detect clinically relevant effects in future clinical trials of feasible size. CONCLUSIONS: Our findings have implications for the choice of primary outcome measure in prion disease clinical trials. Prion disease presents the unusual opportunity to follow patients with a neurodegenerative disease through their entire clinical course, and this provides insights relevant to designing outcome measures in related conditions.

Mechanics of biting in great white and sandtiger sharks.

Although a strong correlation between jaw mechanics and prey selection has been demonstrated in bony fishes (Osteichthyes), how jaw mechanics influence feeding performance in cartilaginous fishes (Chondrichthyes) remains unknown. Hence, tooth shape has been regarded as a primary predictor of feeding behavior in sharks. Here we apply Finite Element Analysis (FEA) to examine form and function in the jaws of two threatened shark species, the great white (Carcharodon carcharias) and the sandtiger (Carcharias taurus). These species possess characteristic tooth shapes believed to reflect dietary preferences. We show that the jaws of sandtigers and great whites are adapted for rapid closure and generation of maximum bite force, respectively, and that these functional differences are consistent with diet and dentition. Our results suggest that in both taxa, insertion of jaw adductor muscles on a central tendon functions to straighten and sustain muscle fibers to nearly orthogonal insertion angles as the mouth opens. We argue that this jaw muscle arrangement allows high bite forces to be maintained across a wider range of gape angles than observed in mammalian models. Finally, our data suggest that the jaws of sub-adult great whites are mechanically vulnerable when handling large prey. In addition to ontogenetic changes in dentition, further mineralization of the jaws may be required to effectively feed on marine mammals. Our study is the first comparative FEA of the jaws for any fish species. Results highlight the potential of FEA for testing previously intractable questions regarding feeding mechanisms in sharks and other vertebrates.

Brain-water diffusion coefficients reflect the severity of inherited prion disease.

OBJECTIVE: Inherited prion diseases are progressive neurodegenerative conditions, characterized by cerebral spongiosis, gliosis, and neuronal loss, caused by mutations within the prion protein (PRNP) gene. We wished to assess the potential of diffusion-weighted MRI as a biomarker of disease severity in inherited prion diseases. METHODS: Twenty-five subjects (mean age 45.2 years) with a known PRNP mutation including 19 symptomatic patients, 6 gene-positive asymptomatic subjects, and 7 controls (mean age 54.1 years) underwent conventional and diffusion-weighted MRI. An index of normalized brain volume (NBV) and region of interest (ROI) mean apparent diffusion coefficient (ADC) for the head of caudate, putamen, and pulvinar nuclei were recorded. ADC histograms were computed for whole brain (WB) and gray matter (GM) tissue fractions. Clinical assessment utilized standardized clinical scores. Mann-Whitney U test and regression analyses were performed. RESULTS: Symptomatic patients exhibited an increased WB mean ADC (p = 0.006) and GM mean ADC (p = 0.024) compared to controls. Decreased NBV and increased mean ADC measures significantly correlated with clinical measures of disease severity. Using a stepwise multivariate regression procedure, GM mean ADC was an independent predictor of Clinician's Dementia Rating score (p = 0.001), Barthel Index of activities of daily living (p = 0.001), and Rankin disability score (p = 0.019). CONCLUSIONS: Brain volume loss in inherited prion diseases is accompanied by increased cerebral apparent diffusion coefficient (ADC), correlating with increased disease severity. The association between gray matter ADC and clinical neurologic status suggests this measure may prove a useful biomarker of disease activity in inherited prion diseases.

The cognitive and psychomotor effects of remacemide and carbamazepine in newly diagnosed epilepsy.

An international trial comparing remacemide hydrochloride with carbamazepine was undertaken in individuals with newly diagnosed epilepsy using a novel double-blind, parallel-group, double triangular sequential design. Patients with two or more partial or generalized tonic-clonic seizures in the previous year were randomized to remacemide or carbamazepine and titrated to a target dose of 600 mg/day. Subsequent dosage adjustments were allowed while maintaining the blind. Repeated assessments of neuropsychological function and mood were carried out using computerized and conventional measures. The trial was completed 20 months after initiation, following the second interim analysis. Efficacy as measured by seizure recurrence showed remacemide to be inferior to carbamazepine. Baseline cognitive and neuropsychological measures showed impairment across the whole patient population. Cognitive/neuropsychological performance at 8, 24, and 48 weeks was compared with that at baseline. Significant deterioration was seen on measures of information processing speed and attention after treatment with carbamazepine. The study data provide evidence for the utility and sensitivity of a number of cognitive assessments, which may be employed in future trials of antiepileptic drugs.

Phenotypic heterogeneity and genetic modification of P102L inherited prion disease in an international series.

The largest kindred with inherited prion disease P102L, historically Gerstmann-Sträussler-Scheinker syndrome, originates from central England, with émigrés now resident in various parts of the English-speaking world. We have collected data from 84 patients in the large UK kindred and numerous small unrelated pedigrees to investigate phenotypic heterogeneity and modifying factors. This collection represents by far the largest series of P102L patients so far reported. Microsatellite and genealogical analyses of eight separate European kindreds support multiple distinct mutational events at a cytosine-phosphate diester-guanidine dinucleotide mutation hot spot. All of the smaller P102L kindreds were linked to polymorphic human prion protein gene codon 129M and were not connected by genealogy or microsatellite haplotype background to the large kindred or each other. While many present with classical Gerstmann-Sträussler-Scheinker syndrome, a slowly progressive cerebellar ataxia with later onset cognitive impairment, there is remarkable heterogeneity. A subset of patients present with prominent cognitive and psychiatric features and some have met diagnostic criteria for sporadic Creutzfeldt-Jakob disease. We show that polymorphic human prion protein gene codon 129 modifies age at onset: the earliest eight clinical onsets were all MM homozygotes and overall age at onset was 7 years earlier for MM compared with MV heterozygotes (P = 0.02). Unexpectedly, apolipoprotein E4 carriers have a delayed age of onset by 10 years (P = 0.02). We found a preponderance of female patients compared with males (54 females versus 30 males, P = 0.01), which probably relates to ascertainment bias. However, these modifiers had no impact on a semi-quantitative pathological phenotype in 10 autopsied patients. These data allow an appreciation of the range of clinical phenotype, modern imaging and molecular investigation and should inform genetic counselling of at-risk individuals, with the identification of two genetic modifiers.

Long-term safety and efficacy of zonisamide in patients with refractory partial-onset epilepsy.

OBJECTIVES: To investigate whether zonisamide remains effective and well tolerated in the treatment of refractory partial epilepsy during long-term treatment and with flexible dosing in clinical practice. MATERIALS AND METHODS: Patients with refractory partial epilepsy who completed a fixed-dose, randomized, double-blind clinical trial were recruited in an open-label extension study with adjustment of zonisamide and other antiepileptic drug dosage according to the treating physician's usual clinical practice. RESULTS: An intention-to-treat analysis of 317 patients showed that zonisamide was well tolerated with a predictable safety profile. Patient retention rates at 1, 2 and 3 years were 65.3%, 44.5% and 28.8%, respectively. Zonisamide treatment was associated with a maintained reduction in seizure frequency, with some patients achieving prolonged periods of seizure freedom. CONCLUSIONS: Flexible dosing with zonisamide demonstrated a good safety profile and sustained efficacy in the long-term adjunctive treatment of refractory partial epilepsy.

Inherited prion disease with 5-OPRI: phenotype modification by repeat length and codon 129.

BACKGROUND: Human prion diseases have sporadic, acquired and inherited etiologies and show considerable phenotypic heterogeneity. An individual inherited prion disease offers an opportunity to study the determinants of this clinicopathologic heterogeneity among individuals with the same causal mutation. METHODS: We report clinical and pathologic data from three families with different 5-octapeptide repeat insertion (5-OPRI) mutations of the prion protein gene (PRNP), extending the reported phenotypic range of this mutation. RESULTS: The proband of a South African family presented with a rapidly progressive dementia and atypical pathology associated with kuru-like prion protein plaques. The original mutation in this family probably occurred on a PRNP allele encoding a 1-octapeptide repeat deletion polymorphism. This has not been previously reported as a precursor allele in over 30 other OPRI mutation kindreds. An English family with a genetically distinct mutation but identical protein product showed clinical onsets that varied 30 years between father and daughter, an effect that may be explained by their genotypes at PRNP codon 129. A patient from Northern Ireland with a phenotype of sporadic Creutzfeldt-Jakob disease presenting with visual disturbance was unexpectedly found to have a 5-OPRI. CONCLUSIONS: When these cases were combined with the existing world literature, the mean age at onset for patients with 5-octapeptide repeat insertion (5-OPRI) was significantly later than that for patients with 6-OPRI, but both mutations exhibit a similar powerful disease modifying effect of PRNP codon 129.

Neuroimaging findings in human prion disease.

Imaging occupies an important role in the investigation of dementia and neurodegenerative disease. The role of imaging in prion disease used to be one of exclusion of other conditions. Over the past decade, the non-invasive nature of MRI, the improved range of magnetic resonance sequences and the availability of clinical and neuropathological correlation have led to a more prominent position of MRI and its inclusion in the diagnostic criteria for variant Creutzfeldt-Jakob disease. As experience of imaging in human prion disease increases, patterns of change related to strain and genotype may improve the diagnostic potential of imaging in the future, may reduce the need for more invasive testing and prove useful in future therapeutic trials. This paper reviews the current knowledge of imaging appearances in human prion disease.

Levetiracetam in a broad population of patients with refractory epilepsy: interim results of the international SKATE trial.

OBJECTIVE: To prospectively assess the safety and efficacy of levetiracetam in patients with uncontrolled focal epilepsy, in a common practice-based setting. PATIENTS AND METHODS: In this phase IV, open-label, 16-week community-based study, adult patients with focal seizures initially received levetiracetam 1,000 mg/day. Throughout the study, the dose was adjusted in increments of 1,000 mg (maximum 3,000 mg/day) to achieve seizure control and maintain tolerability. The outcome parameters were the percentage reduction in partial and total seizure frequency per week from historical baseline, global evaluation scale (GES), and adverse events (AE). RESULTS: Seven hundred and thirty-one patients were included in this analysis and 84.4% completed the study. The median percent reduction in all seizures was 47.8%, and 49.3% for all partial seizures. The 50% responder rate was 49%, and the seizure-free rate was 17.2% for all partial seizures. Approximately 60% of patients showed moderate to marked improvement on the GES. The majority of AE were of mild to moderate severity; the most commonly reported being asthenia, somnolence, headache, and dizziness. CONCLUSION: Levetiracetam is both efficacious and safe as an add-on therapy in patients with refractory epilepsy treated by clinicians in their daily practice.

Serum antibodies in epilepsy and seizure-associated disorders.

OBJECTIVE: To investigate whether autoantibodies to ion channels and other neural antigens are present in the sera of patients with epilepsy and seizure-related diseases. METHODS: Sera were obtained from 139 patients, including 26 with preexisting autoimmune disease, 46 in whom an autoimmune basis was suspected, and 67 with drug-resistant epilepsy. The sera were assayed for antibodies to voltage-gated potassium (VGKC) and calcium (VGCC) channels, glutamic acid decarboxylase (GAD), gangliosides, glutamate receptor type 3, cardiolipins, DNA, and nuclear antigens; the results were compared with results from a large cohort of healthy and disease controls. RESULTS: Increased titers of VGKC antibodies (>100 pM) were detected in 16 of 139 (11%) patients with seizures but only 1 control (0.5%). Eight VGKC-positive patients presented with an acute/subacute illness, and 5 of these had the highest VGKC antibodies; 3 patients improved spontaneously, another 5 patients responded well to immunomodulatory therapy. The other VGKC-positive patients had longer disease duration (>6 years) and intermediate levels of antibodies; immunotherapies have not been tested in this group. Very high levels of GAD antibodies (>1,000 U) were found in an additional 3 patients (2.1%) with long-standing drug-resistant epilepsy. CONCLUSIONS: The presence of autoantibodies to voltage-gated potassium channels and glutamic acid decarboxylase suggests that the immune system may contribute to certain forms of epilepsy or seizure-associated disorders. Further studies are needed to determine whether the antibodies are pathogenic.

Effects of dose titration on tolerability and efficacy of interferon beta-1b in people with multiple sclerosis.

Multiple sclerosis (MS) treatment with interferon beta is associated with well-known, easily managed adverse events, including influenza-like symptoms and injection-site reactions that decline over time. Initial dose titration has been shown to be one way of limiting these adverse events. Hence, a placebo-controlled, multicentre study of 98 patients was set up to explore whether a slower, four-stage, 4-week titration to a final dose of 250 microg subcutaneous interferon beta-1b might improve tolerability over a more rapid two-stage, 2-week titration in patients with relapsing-remitting MS. Frequency of adverse events was found to be similar between the two regimens: notably, no difference in the incidence of injection-site reactions, with a trend towards fewer influenza-like symptoms in the slow-titration group. Relative to placebo, significantly fewer patients receiving interferon beta-1b relapsed. This was more pronounced in the rapid-titration group than in the slow-titration group, showing that rapid and significant improvements in relapse rates were achieved within 90 days of starting interferon beta-1b. Although a rapid-titration regimen results in a quicker onset of clinical benefit, slow titration showed a non-significant trend towards reduced influenza-like symptoms.