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.

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.

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.

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.

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.

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.

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.

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.

Gabapentin does not affect antipyrine clearance.

The effect of gabapentin on antipyrine clearance was assessed in 12 healthy male volunteers, using a known enzyme inducer, phenytoin, as control. Subjects received gabapentin 400 mg or phenytoin 100 mg three times daily for 2 weeks. Antipyrine tests were performed before, during, and after treatment with gabapentin or phenytoin. In contrast to phenytoin, chronic administration of gabapentin did not affect antipyrine clearance. Gabapentin appears to have little potential for drug interactions.

The clinical value of serum prolactin measurement in the differential diagnosis of complex partial seizures.

The time course of changes in serum prolactin after complex partial seizures has been determined and compared to similar changes after other types of seizure and non-epileptic attacks. Seizures in 33 subjects were recorded on video EEG telemetry. Peak serum prolactin concentrations occurred 15-20 min after tonic-clonic seizures, 10 min after complex partial seizures, and were highest after generalised tonic-clonic seizures. Serum prolactin concentrations remained less than 1000 mU/l after absences and non-epileptic attacks. Application of Bayes' theorem showed that where serum prolactin was greater than 1000 mU/l 5-10 min post event this would identify genuine tonic-clonic or complex partial seizures. The false negative rate of this test was 9% for tonic-clonic seizures and 38% for complex partial seizures. Failure of serum prolactin to rise after an attack is of little value in distinguishing complex partial seizures from non-epileptic attacks.

Dose-response effect of levetiracetam 1000 and 2000 mg/day in partial epilepsy.

PURPOSE: To evaluate the efficacy, dose-response, tolerability, and withdrawal effects of levetiracetam (Keppra) as adjunctive therapy in adult patients with partial epilepsy. METHODS: In this European multicenter, double-blind, randomized, cross-over trial, levetiracetam 1000 or 2000 mg/day given in two divided doses was compared to placebo as add-on therapy in 324 patients with refractory partial seizures with or without secondary generalization. This trial consisted of six periods: an 8- or 12-week baseline, a treatment period A (4-week titration and 12-week evaluation), a treatment period B (4-week titration and 12-week evaluation), and a withdrawal period. During each evaluation period (A and B), patients received two of the three possible treatment regimens. RESULTS: This study provides additional information on dose-response effects and withdrawal phenomena and confirms the responder and seizure freedom rates previously reported in the parallel part of the study (Epilepsia 41 (2000) 1179-1186). Both doses of levetiracetam significantly decreased mean partial seizure frequency compared with placebo (P<0.001), and significantly more patients receiving levetiracetam had > or = 50 and > or = 75% reductions in partial seizure frequency (1000 mg, P=0.004 and P=0.043, respectively; 2000 mg P=0.001 and P<0.001, respectively). In addition, 5.5% (10/183) of patients receiving levetiracetam 1000 mg/day and 6.3% (11/175) of patients receiving levetiracetam 2000 mg/day were seizure-free during the corresponding evaluation period, compared with 1.2% (2/172) of patients on placebo. A within-patient comparison revealed a significantly greater responder rate for the higher levetiracetam dose (P=0.018). The most commonly reported adverse effects (> or = 5% and more frequent in one of the groups with levetiracetam) were headache, asthenia, infection, somnolence, pharyngitis, dizziness, and pain. No withdrawal-related adverse events were reported during the cross-titration period. CONCLUSIONS: Levetiracetam was effective and well-tolerated and decreased seizure frequency in a dose-dependent manner, with no evidence of typical withdrawal-related adverse events or rebound phenomena after withdrawal or down-titration.

Cerebrospinal fluid oligoclonal IgM in multiple sclerosis: analytical problems and clinical limitations.

A method for detecting cerebrospinal fluid (CSF) oligoclonal IgM is described. Concentrated CSF was separated by agarose isoelectric-focusing and blotted with poly(vinyldifluoride). A double-antibody immunoperoxidase technique with avidin-biotin amplification was used to stain IgM. Special conditions were required to avoid cross-reaction with IgG. The method was applied to 99 patients on whom oligoclonal IgG analysis was performed. Positive IgM results occurred in 17 of the 27 patients positive for oligoclonal IgG, and in two patients negative for oligoclonal IgG, neither of whom had multiple sclerosis (MS). Fifteen of the patients positive for oligoclonal IgM had some IgM bands in their sera. Oligoclonal IgM was not found in the CSF of suspected MS patients without oligoclonal IgG, but occurred in several patients with oligoclonal IgG due to other diseases. As a test for MS, oligoclonal IgM was less sensitive than oligoclonal IgG and did not improve specificity.

Oligoclonal bands and the IgG index in multiple sclerosis: uses and limitations.

The relationship between two tests commonly used in the investigation of multiple sclerosis (MS), the IgG index and oligoclonal bands, has been assessed. Using an immunoblotting technique specific for IgG, analysis of cerebrospinal fluid for oligoclonal bands was found to provide greater diagnostic sensitivity than the IgG index without any loss of specificity. In patients without oligoclonal bands the IgG index had no diagnostic value for MS and in the presence of bands the magnitude of the index was unrelated to the clinical certainty of the diagnosis. High values of the IgG index were invariably associated with the presence of oligoclonal bands and the IgG index appeared to have no clinical significance independent of this relationship. Even as a screening test the IgG index has serious limitations.

Extraordinary diphyodonty-related change in dental function for a tooth of the extinct marsupial Ekaltadeta ima (Propleopinae, Hypsiprymnodontidae).

A time-dependent, fundamental change in function for a sectorial tooth in a group of extinct, propleopine kangaroos is reported. In juvenile Ekaltadeta ima (Marsupialia, Hypsiprymnodontidae, Propleopinae) the second premolar (P2) functions as a serrated blade at the anterior end of the cheek tooth row. In adults, this tooth drops far below the occlusal plane of the cheek tooth row where it assumes a completely different function, that of a buttress, anterolingual to the base of the crown of the much larger, newly erupted third premolar (P3). This pattern of diphyodonty-related change in dental function is unique within Mammalia. It also represents an extraordinary example of biological recycling of a normally discarded tooth.

Remacemide hydrochloride as an add-on therapy in epilepsy: a randomized, placebo-controlled trial of three dose levels (300, 600 and 1200 mg/day) in a Q.I.D. regimen.

Remacemide hydrochloride is a low-affinity, non-competitive N-methyl-D-aspartic acid (NMDA) receptor channel blocker, under investigation in epilepsy. This double-blind, placebo-controlled, multicentre study assessed the safety and efficacy of remacemide hydrochloride or placebo, as adjunctive therapy, in 252 adult patients with refractory epilepsy who were already taking up to three antiepileptic drugs (including an enzyme-inducer). Patients were randomized to one of three doses of remacemide hydrochloride (300, 600 or 1200 mg /day) or placebo Q.I.D., for up to 15 weeks. An increasing percentage of responders (defined as a reduction in seizure frequency from baseline of > or =50%) was seen with increasing remacemide hydrochloride dose. At 1200 mg /day, 23% of patients were responders compared with 7% on placebo. This difference was significant (P = 0.016), as was the overall difference between treatments (P = 0.038). Adverse events: dizziness, abnormal gait, gastrointestinal disturbance, somnolence, diplopia and fatigue were mild or moderate in severity. Carbamazepine and phenytoin plasma concentrations were well controlled and maintained within target ranges, with no evidence of improved seizure control due to increases in the concentrations of these drugs. A dose-dependent, significant, increase in responders following adjunctive remacemide hydrochloride compared with placebo was observed. Remacemide hydrochloride was well tolerated.

Diurnal variation in incidence of stroke: Oxfordshire community stroke project.

OBJECTIVE: To determine whether diurnal variation occurs in the onset of stroke. DESIGN: Community based study over four years. SETTING: Oxfordshire, United Kingdom. SUBJECTS: 105,000 people, of whom 675 had a first ever stroke. 545 had a cerebral infarction, 66 had primary intracerebral haemorrhage, 33 had subarachnoid haemorrhage, and in 31 the type of stroke was not known. MAIN OUTCOME MEASURES: Time of stroke and degree of activity at onset. RESULTS: In the 578 patients for whom it was known whether onset occurred while asleep or awake, the proportion with onset during sleep was 25% (135/545) for cerebral infarction, 17% (11/66) for primary intracerebral haemorrhage, and 0% (0/33) for subarachnoid haemorrhage. This difference persisted if patients in whom it was not known whether they were asleep or awake at onset were classed as asleep. For all stroke types together there was a significant (chi 2 = 218.7, p less than 0.001) diurnal variation with a morning peak between 0800 and 1000, which persisted even after allowing for strokes first noted on waking by redistributing the hour of onset through the preceding eight hours (chi 2 = 47, p less than 0.001). A significant diurnal variation was also found in the onset of cerebral infarction (peak 0800-1000, chi 2 = 208.4, p less than 0.001). Fewer patients had other forms of stroke and the diurnal variations for primary intracerebral haemorrhage (peak 1000-1200) and subarachnoid haemorrhage (peaks 0800-1000 and 1800-2000) were not significant. There seemed to be a second smaller peak for all types of stroke. CONCLUSIONS: All types of stroke are most likely to occur after waking in the morning. The cause of the circadian variation requires further study.