Cell loss in the motor and cingulate cortex correlates with symptomatology in Huntington's disease

Huntington's disease is an autosomal dominant inherited neurodegenerative disease with motor symptoms that are variably co-expressed with mood and cognitive symptoms, and in which variable neuronal degeneration is also observed in the basal ganglia and the cerebral cortex. We have recently shown that the variable symptomatology in Huntington's disease correlates with the variable compartmental pattern of GABAA receptor and cell loss in the striatum. To determine whether the phenotypic variability in Huntington's disease is also related to variable neuronal degeneration in the cerebral cortex, we undertook a double-blind study using unbiased stereological cell counting methods to determine the pattern of cell loss in the primary motor and anterior cingulate cortices in the brains of 12 cases of Huntington's disease and 15 controls, and collected detailed data on the clinical symptomatology of the patients with Huntington's disease from family members and clinical records. The results showed a significant association between: (i) pronounced motor dysfunction and cell loss in the primary motor cortex; and (ii) major mood symptomatology and cell loss in the anterior cingulate cortex. This association held for both total neuronal loss (neuronal N staining) and pyramidal cell loss (SMI32 staining), and also correlated with marked dystrophic changes in the remaining cortical neurons. There was also an association between cortical cell loss and striatal neuropathological grade, but no significant association with CAG repeat length in the Huntington's disease gene. These findings suggest that the heterogeneity in clinical symptomatology that characterizes Huntington's disease is associated with variation in the extent of cell loss in the corresponding functional regions of the cerebral cortex whereby motor dysfunction correlates with primary motor cortex cell loss and mood symptomatology is associated with cell loss in the cingulate corte

The clinical features of the piriformis syndrome: a systematic review

Piriformis syndrome, sciatica caused by compression of the sciatic nerve by the piriformis muscle, has been described for over 70 years; yet, it remains controversial. The literature consists mainly of case series and narrative reviews. The objectives of the study were: first, to make the best use of existing evidence to estimate the frequencies of clinical features in patients reported to have PS; second, to identify future research questions. A systematic review was conducted of any study type that reported extractable data relevant to diagnosis. The search included all studies up to 1 March 2008 in four databases: AMED, CINAHL, Embase and Medline. Screening, data extraction and analysis were all performed independently by two reviewers. A total of 55 studies were included: 51 individual and 3 aggregated data studies, and 1 combined study. The most common features found were: buttock pain, external tenderness over the greater sciatic notch, aggravation of the pain through sitting and augmentation of the pain with manoeuvres that increase piriformis muscle tension. Future research could start with comparing the frequencies of these features in sciatica patients with and without disc herniation or spinal stenosis

Evolution of late steps in exocytosis:conservation and specialization of the exocyst complex

Background: The eukaryotic endomembrane system most likely arose via paralogous expansions of genes encoding proteins that specify organelle identity, coat complexes and govern fusion specificity. While the majority of these gene families were established by the time of the last eukaryotic common ancestor (LECA), subsequent evolutionary events has moulded these systems, likely reflecting adaptations retained for increased fitness. As well as sequence evolution, these adaptations include loss of otherwise canonical components, the emergence of lineage-specific proteins and paralog expansion. The exocyst complex is involved in late exocytosis and additional trafficking pathways and a member of the complexes associated with tethering containing helical rods (CATCHR) tethering complex family. CATCHR includes the conserved oligomeric Golgi (COG) complex, homotypic fusion and vacuole protein sorting (HOPS)/class C core vacuole/endosome tethering (CORVET) complexes and several others. The exocyst is integrated into a complex GTPase signalling network in animals, fungi and other lineages. Prompted by discovery of Exo99, a non-canonical subunit in the excavate protist Trypanosoma brucei, and availability of significantly increased genome sequence data, we re-examined evolution of the exocyst. Methods: We examined the evolution of exocyst components by comparative genomics, phylogenetics and structure prediction. Results: The exocyst composition is highly conserved, but with substantial losses of subunits in the Apicomplexa and expansions in Streptophyta plants, Metazoa and land plants, where for the latter, massive paralog expansion of Exo70 represents an extreme and unique example. Significantly, few taxa retain a partial complex, suggesting that, in general, all subunits are probably required for functionality. Further, the ninth exocyst subunit, Exo99, is specific to the Euglenozoa with a distinct architecture compared to the other subunits and which possibly represents a coat system. Conclusions: These data reveal a remarkable degree of evolutionary flexibility within the exocyst complex, suggesting significant diversity in exocytosis mechanisms. </p

Metacarpophalangeal joint loads during bonobo locomotion: model predictions vs. proxies

The analysis of internal trabecular and cortical bone has been an informative tool for drawing inferences about behaviour in extant and fossil primate taxa. Within the hand, metacarpal bone architecture has been shown to correlate well with primate locomotion; however, the extent of morphological differences across taxa is unexpectedly small given the variability in hand use. One explanation for this observation is that the activity-related differences in the joint loads acting on the bone are simply smaller than estimated based on commonly used proxies (i.e. external loading and joint posture), which neglect the influence of muscle forces. In this study, experimental data and a musculoskeletal finger model are used to test this hypothesis by comparing differences between climbing and knuckle-walking locomotion of captive bonobos (Pan paniscus) based on (i) joint load magnitude and direction predicted by the models and (ii) proxy estimations. The results showed that the activity-related differences in predicted joint loads are indeed much smaller than the proxies would suggest, with joint load magnitudes being almost identical between the two locomotor modes. Differences in joint load directions were smaller but still evident, indicating that joint load directions might be a more robust indicator of variation in hand use than joint load magnitudes. Overall, this study emphasizes the importance of including muscular forces in the interpretation of skeletal remains and promotes the use of musculoskeletal models for correct functional interpretations

Evidence for habitual climbing in a Pleistocene hominin in South Africa

Bipedalism is a defining trait of the hominin lineage, associated with a transition from a more arboreal to a more terrestrial environment. While there is debate about when modern human-like bipedalism first appeared in hominins, all known South African hominins show morphological adaptations to bipedalism, suggesting that this was their predominant mode of locomotion. Here we present evidence that hominins preserved in the Sterkfontein Caves practiced two different locomotor repertoires. The trabecular structure of a proximal femur (StW 522) attributed to Australopithecus africanus exhibits a modern human-like bipedal locomotor pattern, while that of a geologically younger specimen (StW 311) attributed to either Homo sp. or Paranthropus robustus exhibits a pattern more similar to nonhuman apes, potentially suggesting regular bouts of both climbing and terrestrial bipedalism. Our results demonstrate distinct morphological differences, linked to behavioral differences between Australopithecus and later hominins in South Africa and contribute to the increasing evidence of locomotor diversity within the hominin clade

The deep trabecular structure of first metacarpals in extant hominids

Objectives: Recent studies have associated subarticular trabecular bone distribution in the extant hominid first metacarpal (Mc1) with observed thumb use, to infer fossil hominin thumb use. Here, we analyze the entire Mc1 to test for interspecific differencesin: (1) the absolute volume of trabecular volume fraction, (2) the distribution ofthe deeper trabecular network, and (3) the distribution of trabeculae in the medullarycavity, especially beneath the Mc1 disto-radial flange. Materials and Methods: Trabecular bone was imaged using micro-computed tomography in a sample of Homo sapiens (n = 11), Pan paniscus (n = 10), Pan troglodytes(n = 11), Gorilla gorilla (n = 10) and Pongo sp., (n = 7). Using Canonical Holistic Morphometric Analysis (cHMA), we tested for interspecific differences in the trabecular bone volume fraction (BV/TV) and its relative distribution (rBV/TV) throughout the Mc1, including within the head, medullary cavity, and base. Results: P. paniscus had the highest, and H. sapiens the lowest, BV/TV relative to other species. rBV/TV distribution statistically distinguished the radial concentrations and lack of medullary trabecular bone in the H. sapiens Mc1 from all other hominids. H. sapiens and, to a lesser extent, G. gorilla also had a significantly higher trabecular volume beneath the disto-radial flange relative to other hominids. Discussion: These results are consistent with differences in observed thumb use in these species and may also reflect systemic differences in bone volume fraction. The trabecular bone extension into the medullary cavity and concentrations beneath the disto-radial flange may represent crucial biomechanical signals that will aid in the inference of fossil hominin thumb use

Musculoskeletal models of a human and bonobo finger: parameter identification and comparison to in vitro experiments

Introduction: Knowledge of internal finger loading during human and non-human primate activities such as tool use or knuckle-walking has become increasingly important to reconstruct the behaviour of fossil hominins based on bone morphology. Musculoskeletal models have proven useful for predicting these internal loads during human activities, but load predictions for non-human primate activities are missing due to a lack of suitable finger models. The main goal of this study was to implement both a human and a representative non-human primate finger model to facilitate comparative studies on metacarpal bone loading. To ensure that the model predictions are sufficiently accurate, the specific goals were: (1) to identify species-specific model parameters based on in vitro measured fingertip forces resulting from single tendon loading and (2) to evaluate the model accuracy of predicted fingertip forces and net metacarpal bone loading in a different loading scenario. Materials & Methods: Three human and one bonobo (Pan paniscus) fingers were tested in vitro using a previously developed experimental setup. The cadaveric fingers were positioned in four static postures and load was applied by attaching weights to the tendons of the finger muscles. For parameter identification, fingertip forces were measured by loading each tendon individually in each posture. For the evaluation of model accuracy, the extrinsic flexor muscles were loaded simultaneously and both the fingertip force and net metacarpal bone force were measured. The finger models were implemented using custom Python scripts. Initial parameters were taken from literature for the human model and own dissection data for the bonobo model. Optimized model parameters were identified by minimizing the error between predicted and experimentally measured fingertip forces. Fingertip forces and net metacarpal bone loading in the combined loading scenario were predicted using the optimized models and the remaining error with respect to the experimental data was evaluated. Results. The parameter identification procedure led to minor model adjustments but considerably reduced the error in the predicted fingertip forces (root mean square error reduced from 0.53/0.69 N to 0.11/0.20 N for the human/bonobo model). Both models remained physiologically plausible after the parameter identification. In the combined loading scenario, fingertip and net metacarpal forces were predicted with average directional errors below 6◦ and magnitude errors below 12%. Conclusions. This study presents the first attempt to implement both a human and nonhuman primate finger model for comparative palaeoanthropological studies. The good agreement between predicted and experimental forces involving the action of extrinsic flexors—which are most relevant for forceful grasping—shows that the models are likely sufficiently accurate for comparisons of internal loads occurring during human and non-human primate manual activities

C9ORF72 and UBQLN2 are genetic causes of ALS in New Zealand:A genetic and pathological study using banked human brain tissue

Abstract Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disease which causes progressive and eventually fatal loss of motor function. Here we describe genetic and pathological characterisation of brain tissue banked from 19 ALS patients over nearly 20 years at the Department of Anatomy and the Centre for Brain Research, University of Auckland, New Zealand. We screened for mutations in SOD1, TARDBP, FUS, and C9ORF72 genes, and for neuropathology caused by phosphorylated TDP-43, dipeptide repeats and ubiquilin. We identified two cases with C9ORF72 repeat expansions. Both harboured phosphorylated TDP-43 and dipeptide repeat inclusions. We show that dipeptide repeat inclusions can incorporate or occur independently of ubiquilin. We also identified one case with a UBQLN2 mutation, which showed phosphorylated TDP-43 and characteristic ubiquilin protein inclusions. This is the first study of ALS genetics in New Zealand, adding New Zealand to the growing list of countries in which C9ORF72 repeat expansion and UBQLN2 mutations are detected in ALS cases

Gas mixing enhanced by power modulations in atmospheric pressure microwave plasma jet

Microwave plasma jet operating in atmospheric pressure argon was power modulated by audio frequency sine envelope in the 10^2 W power range. Its effluent was imaged using interference filters and ICCD camera for several different phases of the modulating signal. The combination of this fast imaging with spatially resolved optical emission spectroscopy provides useful insights into the plasmachemical processes involved. Phase-resolved schlieren photography was performed to visualize the gas dynamics. The results show that for higher modulation frequencies the plasma chemistry is strongly influenced by formation of transient flow perturbation resembling a vortex during each period. The perturbation formation and speed are strongly influenced by the frequency and power variations while they depend only weakly on the working gas flow rate. From application point of view, the perturbation presence significantly broadened lateral distribution of active species, effectively increasing cross-sectional area suitable for applications