MSR1 repeats modulate gene expression and affect risk of breast and prostate cancer.

Background: MSR1 repeats are a 36-38 bp minisatellite element that have recently been implicated in the regulation of gene expression, through copy number variation (CNV). Patients and methods: Bioinformatic and experimental methods were used to assess the distribution of MSR1 across the genome, evaluate the regulatory potential of such elements and explore the role of MSR1 elements in cancer, particularly non-familial breast cancer and prostate cancer. Results: MSR1s are predominately located at chromosome 19 and are functionally enriched in regulatory regions of the genome, particularly regions implicated in short-range regulatory activities (H3K27ac, H3K4me1 and H3K4me3). MSR1-regulated genes were found to have specific molecular roles, such as serine-protease activity (P = 4.80 × 10-7) and ion channel activity (P = 2.7 × 10-4). The kallikrein locus was found to contain a large number of MSR1 clusters, and at least six of these showed CNV. An MSR1 cluster was identified within KLK14, with 9 and 11 copies being normal variants. A significant association with the 9-copy allele and non-familial breast cancer was found in two independent populations (P = 0.004; P = 0.03). In the white British population, the minor allele conferred an increased risk of 1.21-3.51 times for all non-familial disease, or 1.7-5.3 times in early-onset disease. The 9-copy allele was also found to be associated with increased risk of prostate cancer in an independent population (odds ratio = 1.27-1.56; P =0.009). Conclusions: MSR1 repeats act as molecular switches that modulate gene expression. It is likely that CNV of MSR1 will affect risk of development of various forms of cancer, including that of breast and prostate. The MSR1 cluster at KLK14 represents the strongest risk factor identified to date in non-familial breast cancer and a significant risk factor for prostate cancer. Analysis of MSR1 genotype will allow development of precise stratification of disease risk and provide a novel target for therapeutic agents.

A pre-operative clinical model to predict microvascular invasion and long-term outcome after resection of hepatocellular cancer: The Australian experience.

BACKGROUND: Hepatocellular cancer (HCC) is a leading cause of mortality worldwide. Liver resection or transplantation offer the best chance of long-term survival. The aim of this study was to perform a survival and prognostic factor analysis on patients who underwent resection of HCC at two major tertiary referral hospitals, and to investigate a pre-operative prediction model for microvascular invasion (MVI). METHODS: Clinico-pathological and survival data were collected from all patients who underwent liver resection for HCC at two tertiary referral centres (Royal North Shore/North Shore Private Hospitals and Westmead Hospital) from 1998 to 2012. An overall and disease-free survival analysis was performed and a predictive model for MVI identified. RESULTS: The total number of patients in this series was 125 and the 5-year overall and disease-free survival rates were 56% and 37%, respectively. MVI was the only factor to be independently associated with a poor prognosis on both overall and disease-free survival. Age ≥64 years, a serum alpha-fetoprotein (AFP) ≥400 ng/ml (×40 above normal) and tumor size ≥50 mm were independently associated with MVI. An MVI prediction model using these three pre-operative factors provides a good assessment of the risk of MVI. CONCLUSION: MVI in the resected specimen of patients with HCC is associated with a poor prognosis. A preoperative MVI prediction model offers a useful way to identify patients at risk of relapse. However, more precise predictive models using molecular and genetic variables are needed to improve selection of patients most suitable for radical surgical treatment.

A novel and simple test of gait adaptability predicts gold standard measures of functional mobility in stroke survivors.

BACKGROUND: Although there is evidence that stroke survivors have reduced gait adaptability, the underlying mechanisms and the relationship to functional recovery are largely unknown. We explored the relationships between walking adaptability and clinical measures of balance, motor recovery and functional ability in stroke survivors. METHODS: Stroke survivors (n=42) stepped to targets, on a 6m walkway, placed to elicit step lengthening, shortening and narrowing on paretic and non-paretic sides. The number of targets missed during six walks and target stepping speed was recorded. Fugl-Meyer (FM), Berg Balance Scale (BBS), self-selected walking speed (SWWS) and single support (SS) and step length (SL) symmetry (using GaitRite when not walking to targets) were also assessed. Stepwise multiple-linear regression was used to model the relationships between: total targets missed, number missed with paretic and non-paretic legs, target stepping speed, and each clinical measure. RESULTS: Regression revealed a significant model for each outcome variable that included only one independent variable. Targets missed by the paretic limb, was a significant predictor of FM (F(1,40)=6.54, p=0.014,). Speed of target stepping was a significant predictor of each of BBS (F(1,40)=26.36, p<0.0001), SSWS (F(1,40)=37.00, p<0.0001). No variables were significant predictors of SL or SS asymmetry. DISCUSSION: Speed of target stepping was significantly predictive of BBS and SSWS and paretic targets missed predicted FM, suggesting that fast target stepping requires good balance and accurate stepping demands good paretic leg function. The relationships between these parameters indicate gait adaptability is a clinically meaningful target for measurement and treatment of functionally adaptive walking ability in stroke survivors.

Foot rotation contribution to trunk and gaze stability during whole-body mediated gaze shifts: a principal component analysis study.

Large gaze displacements are mediated by combined motion of the eye, head, trunk, and foot. We applied principal component analysis (PCA) to examine the degree of variability and linearity in the angular velocity pattern of the various segments involved that participate in this task. Ten normal subjects stood up and had to visually fixate and realign their bodies with LED targets separated 45 degrees apart, ranging from +/-45 to 360 degrees. The outbound movement in this paradigm is unpredictable whereas the return (inbound) movement occurs under spatially predictable conditions. Under such predictable conditions, subjects generate in approximately 15% of the trials gaze shifts, with periods of fairly constant high gaze velocity (single-step gaze shifts). PCA showed that gaze velocity variability did not change if the feet were rotating or not. Foot velocity was variable and showed additional PCs suggestive of non-linear motion components. Trunk and head-in-space velocity showed intermediate levels of variability but its variability decreased during the foot stepping movements. The results suggest that the feet, trunk, and head are less tightly controlled by the central nervous system than gaze velocity. Movements of the feet seem to aid trunk stability and motion rather than gaze control.

Evidence that older adult fallers prioritise the planning of future stepping actions over the accurate execution of ongoing steps during complex locomotor tasks.

Previous research has highlighted differences between older adults determined to be at a low-risk of falling (low-risk) and older adults prone to falling (high-risk) in both where and when they look at stepping targets and the precision with which they subsequently step. On the basis of these findings, we proposed that high-risk older adults prioritise the planning of future stepping actions over the accurate execution of ongoing movements and that adoption of this strategy contributes to increased likelihood of falls. The present experiment was designed to test this hypothesis by manipulating the complexity of the required walking conditions and comparing gaze and stepping performance between young, high-risk and low-risk older adults. Participants walked at a self-selected pace along a 7-m pathway and encountered one of three obstacle conditions: (1) a single stepping target, (2) two stepping targets, (3) two stepping targets separated by a raised obstacle. On average, when there was a single target (Target 1) in the travel path, all groups fixated the target until after heel contact. However, when challenged with additional impending stepping constraints, high-risk older adults transferred their gaze significantly sooner from Target 1 prior to heel contact. On average, low-risk older adults and younger adults maintained gaze on Target 1 until after heel contact, irrespective of future constraints. Premature gaze transfer was associated with decline in stepping accuracy and precision. Our findings suggest that high-risk older adults choose a potentially hazardous gaze strategy when challenged with multiple obstacles. Putative mechanisms underlying this behaviour are discussed.

Age-related differences in stepping performance during step cycle-related removal of vision.

The aim of the present study was to investigate whether there are age-related changes in the ability of individuals to use vision to plan (feedforward control) and guide (on-line control) foot placement during locomotion. This aim was achieved by constraining the availability of vision and comparing the effects on the stepping performances of older and young adults during a precision stepping task. We experimentally controlled the availability of visual information such that: (1) vision was only available during each stance phase of the targeting limb, (2) vision was only available during each swing phase of the targeting limb or (3) vision was always available. Our visual manipulations had relatively little effect on younger adults' stepping performance as demonstrated by their missing the target on less than 10% of occasions. However, there were clear visual condition-related differences in older adults' stepping performance. When vision was only available during the stance phase of the targeting limb, older adults demonstrated significantly larger foot placement error and associated task failure rate (23%) than trials in which vision was always available (10%). There was an even greater increase in older adults' foot placement error and task failure rate (42%) during trials in which vision was only available in the swing phase than the other visual conditions. These findings suggest that older adults need vision at particular times during the step cycle, to effectively pre-plan future stepping movements. We discuss the evidence that these age-related changes in performance reflect decline in visual and visuomotor CNS pathways.

Surgeons' participation in continuing medical education: is it evidence-based?

BACKGROUND: Interactive forms of continuing medical education (CME) are more likely to improve clinical practice than traditional, passive approaches. This study investigated CME participation and preferences among surgeons. METHOD: Questionnaire survey of surgeons in New South Wales, Australia. RESULTS: On average, respondents (n = 418, 77% response rate) committed 364 hours (interquartile range 228-512 hours) to CME per year. Surgeons working at tertiary referral teaching hospitals were twice as likely as those working in other types of hospital to report spending more than 12 hours per month on CME (OR 2.1, 95% CI: 1.4-3.1). Overall, reading accounted for 17% of CME time and attending conferences a further 12%. Clinical audit accounted for significantly less CME time (3.5%) (both P < 0.001). Conferences were considered the single most useful form of CME by 28% (95% CI: 24-33%). Over half (55%, 95% CI: 50-59%) ranked reading as 1 of the 3 most useful types of CME, whereas significantly fewer so ranked clinical audit (6%, 95% CI: 4-9%) (chi2 = 230.8, 1 d.f., P < 0.001). CONCLUSION: Australian surgeons commit a considerable amount of time to CME, but much of this time is spent in passive educational activities. Development of acceptable and effective CME programmes will benefit both surgeons and their patients.

Evidence for a link between changes to gaze behaviour and risk of falling in older adults during adaptive locomotion.

There is increasing evidence that gaze stabilization with respect to footfall targets plays a crucial role in the control of visually guided stepping and that there are significant changes to gaze behaviour as we age. However, past research has not measured if age-related changes in gaze behaviour are associated with changes to stepping performance. This paper aims to identify differences in gaze behaviour between young (n=8) adults, older adults determined to be at a low-risk of falling (low-risk, n=4) and older adults prone to falling (high-risk, n=4) performing an adaptive locomotor task and attempts to relate observed differences in gaze behaviour to decline in stepping performance. Participants walked at a self-selected pace along a 9m pathway stepping into two footfall target locations en route. Gaze behaviour and lower limb kinematics were recorded using an ASL 500 gaze tracker interfaced with a Vicon motion analysis system. Results showed that older adults looked significantly sooner to targets, and fixated the targets for longer, than younger adults. There were also significant differences in these measures between high and low-risk older adults. On average, high-risk older adults looked away from targets significantly sooner and demonstrated less accurate and more variable foot placements than younger adults and low-risk older adults. These findings suggest that, as we age, we need more time to plan precise stepping movements and clearly demonstrate that there are differences between low-risk and high-risk older adults in both where and when they look at future stepping targets and the precision with which they subsequently step. We propose that high-risk older adults may prioritize the planning of future actions over the accurate execution of ongoing movements and that adoption of this strategy may contribute to an increased likelihood of falls.

"Look where you're going!": gaze behaviour associated with maintaining and changing the direction of locomotion.

In order to fully understand how vision is used to guide locomotion it is necessary to know what people look at as they move through the environment. This study provides information, hitherto lacking, regarding gaze behaviour associated with both maintaining and changing the direction of locomotion: activities that are essential for efficient navigation through our cluttered environment. Participants' spatiotemporal gaze patterns were recorded whilst they performed a task requiring that they either maintained a straight walking trajectory or changed their direction of walking by 30 degrees or 60 degrees, left or right, at the midpoint of a 9-m path. Participants were either visually cued to turn when they stepped on a trigger mat placed one step before the mid-point of the walkway (cued trials) or given verbal instruction about the required route prior to the start of each trial (advance knowledge trials). Our clear finding was that for the large majority of the time participants' gaze was aligned with environmental features lying in their current plane of progression both prior to and following the onset of the transition stride during which the direction change was implemented. This gaze behaviour was observed both during cued trials (78% of total fixation time prior to the transition stride onset and 89% following the transition stride onset) and advance knowledge trials (67% prior to transition stride onset, 92% following transition stride onset). When not aligned with the plane of progression, gaze was normally fixated on environmental features related to either known or potential future routes. Prior to changing the direction of walking, individuals invariably made saccadic eye movements in order to align gaze with the end-point of the required travel path. This gaze realignment was invariably accompanied by head reorientation, which was initiated, on average, at the same time as the saccade. On average, participants fixated gaze on their goal (represented by the cue light at the travel path end-point) until after head realignment with the new path was achieved. Additionally, the head was consistently aligned with participants' current walking direction prior to and following the transition stride even on the minority of occasions when they were looking elsewhere. These findings challenge the ecological validity of existing theories of how visual information is used to determine heading direction and are consistent with the proposal that aligning the head with the desired travel direction through coordinated eye and head movements provides the CNS with an allocentric frame of reference that is used to control the movement of the body in space.

Effects of head immobilization on the coordination and control of head and body reorientation and translation during steering.

Changing the direction of locomotion involves lateral translation of the body in addition to body reorientation to align with the new travel direction. We designed this study to investigate the CNS control of these postural adjustments. The specific aims of the study were: first, to test the hypothesis that anticipatory head movements towards the new travel path are proactively controlled by the CNS to provide a stable frame of reference for body reorientation and, second, to investigate the relative contribution of foot placement and other mechanisms to the control of lateral body translation during steering. We achieved these aims by carrying out a comprehensive biomechanical analysis of participants performing a steering paradigm and observing the effects of immobilizing the head (by fixing it to the trunk) on postural control and the sequencing of body segment reorientation. Participants performed a task whereby they were visually cued to change their direction of walking by 30 degrees or 60 degrees, left or right, at the midpoint of a 9-m path. The temporal sequence of body reorientation was consistent with previous findings that the head starts to turn in the direction of travel before the rest of the body. Translation of the centre of mass (COM) in the new travel direction was achieved both through alternate placement of the contralateral foot prior to the turn step and use of a hip strategy to control the body pendulum during swing. Immobilizing the head resulted in the following significant changes: earlier onset of trunk yaw with respect to cue delivery, later trunk roll onset and a reduction in trunk roll amplitude. These results provide valuable information regarding the biomechanics of steering and support the hypothesis that aligning the head with motor or locomotor goals using vision provides the CNS with a stable frame of reference, independent of gaze, that can be used to control the repositioning of the body in space.

Coordination of eye and leg movements during visually guided stepping.

In the present study, 2 related hypotheses were tested: first, that vision is used in a feedforward control mode during precision stepping onto visual targets and, second, that the oculomotor and locomotor control centers interact to produce coordinated eye and leg movements during that task. Participants' (N = 4) eye movements and step cycle transition events were monitored while they performed a task requiring precise foot placement at every step onto irregularly placed stepping stones under conditions in which the availability of visual information was either restricted or intermittently removed altogether. Accurate saccades, followed by accurate steps, to the next footfall target were almost always made even when the information had been invisible for as long as 500 ms. Despite delays in footlift caused by the temporary removal (and subsequent reinstatement) of visual information, the mean interval between the start of the eye movement and the start of the swing toward a target did not vary significantly (p >.05). In contrast, the mean interval between saccade onset away from a target and a foot landing on that target (stance onset) did vary significantly (p <.05) under the different experimental conditions. Those results support the stated hypotheses.

Evidence for interactive locomotor and oculomotor deficits in cerebellar patients during visually guided stepping.

Eight patients suffering from primary cerebellar degenerative diseases undertook a walkway task, demanding precise foot placement at each step, and a visual fixation task, requiring only eye movements. Step cycle and horizontal eye movements were recorded throughout the tasks and compared to those of healthy adults (including age- and sex-matched controls). Cerebellar patients displayed both locomotor and oculomotor deficits. Increases in duration of the stance, swing and double support phases of the step cycle were all shown to contribute to ataxic gait. Dysmetric saccades to fixate the footfall targets were seen more frequently in patients than in controls. These hypometric saccades were followed by one or more corrective saccades (patients: >45% accompanied by one or more corrective saccades; controls: <10% accompanied by a single corrective saccade). Similarities between the oculomotor deficits displayed by patients during the visual fixation task and when walking indicate that the latter are not merely a consequence of ataxic gait. The existence of several links between these locomotor and oculomotor deficits provides evidence for considerable interaction between the two control systems in the production of patterned eye and stepping movements. These results also suggest that the cerebellum plays an active role in the co-ordination of visually guided eye and limb movements during visually guided stepping.

Use of spiral and non-spiral computed tomography arterial portography in the detection of potentially malignant liver masses.

The present study assesses the usefulness of computed tomography (CT) arterial portography (CTAP) in detecting and defining the number and anatomy of potentially malignant liver lesions. One hundred and one adults studied in 1993 and 1994 were retrospectively reviewed, including patients with primary or secondary tumours for possible resection and patients with non-hepatic malignancies in whom the detection of liver metastases would preclude surgery. Twenty-three patients underwent non-spiral CT studies and 78 had studies on a spiral unit, with 22 of these having single phase and 56 having dual phase studies to overcome artefact problems. The relationship between lesion size and detection sensitivity is critical. On non-spiral studies, the overall lesion detection sensitivity and positive predictive value was 69 and 90%, respectively. Detection sensitivity was 100 and 20% for lesions > 1 cm and < 1 cm, respectively. On single phase spiral CTAP the overall detection sensitivity and positive predictive value was 80 and 66%, respectively. Detection sensitivity for lesions > 1 cm and < 1 cm was 100 and 0%, respectively. On dual phase spiral CTAP the overall detection sensitivity and positive predictive value was 76 and 71%, respectively. For lesions > 1 cm and < 1 cm the sensitivity was 81 and 55%, respectively. Eighteen patients with non-hepatic malignancies with unsuspected metastatic spread did not proceed to major surgery because of liver metastases detected on CTAP. Perfusion artefacts occurred in 30 and 64% of non-spiral and of initial portal venous spiral CTAP studies, respectively. By using the double-phase technique, these artefacts were substantially diminished. In conclusion, CTAP is a valuable tool for assessing the presence, site and size of possible liver tumours and confers a benefit even when previous ultrasound and conventional CT have already been used. In addition, CTAP has a lower limit of useful resolution of approximately 1 cm. Perfusion artefacts can be reduced by a dual phase protocol.

Intercostal pedicle flap for thoracic oesophageal perforations.

Oesophageal perforations are associated with a high mortality and morbidity. Intrathoracic perforations especially are associated with mediastinitis and sepsis. The repair of these perforations may be difficult, particularly when there has been a delay to diagnosis. We report our use of a method to repair or buttress the suture line after repair with a vascularized intercostal muscle flap, having used it successfully in two patients with intrathoracic oesophageal perforations.

A method for automatic identification of saccades from eye movement recordings.

We describe a technique for reliable and rapid automatic identification of saccades in eye movement records. The signal processing that we describe will be useful to anyone wanting to analyse large numbers (thousands) of eye movements. We describe a transform that is derived from the differentiated eye movement record, and which is related to a transform previously used to automate analysis of EMG recordings.

Visually guided stepping under conditions of step cycle-related denial of visual information.

We recently reported that subjects performing a task that requires visual guidance of each step onto irregularly placed "stepping stones" usually fixate the next target of footfall just before they lift the foot to be repositioned, i.e. towards the end of that limb's stance phase. When negotiating the same walkway without ambient lighting, and with each stone's location indicated by a central light spot (LED), stepping and eye movements were unchanged. Under conditions of intermittent visual denial, in which all LEDs (the only visual cues) were temporarily extinguished at irregular intervals, temporal changes in the normal stepping pattern were sometimes observed, but stepping was not always affected. The primary effect of visual denial was on the leg that was in stance (foot in place on a stepping stone) at the moment of LED extinction, rather than on the leg that was in swing, and was an increase in stance duration, suggesting an effect on planning during this stance of the next swing towards the next target rather than on execution of the ongoing swing of the other leg. Subjects rarely failed to step onto the targets. Prolongations of stance under visual denial lasting 400 or 500 ms were less than 200 ms, much less than the duration of denial; subjects did not simply wait for the footfall target to reappear. There was no effect for denial lasting 300 ms; subjects performed as well as with a constantly visible target. Under 400 and 500 ms denial, there was no effect when the targets disappeared in the first 100 ms of stance (of the foot to be repositioned); stance durations were indistinguishable from control. This suggests that there is no crucial visuomotor processing by the control system(s) for eye and limb guidance until the target reappeared near the usual end of stance, when feedforward planning of the next saccade and/or swing to a target reaches a crucial stage, and is affected by intrusion of the period of visual denial. With longer (800 ms) denial there was an effect regardless of when in stance it began. A smaller effect of 800 ms denial sometimes visible in swing duration is attributable to interlimb coordination. Accurate saccades, followed by accurate steps, to the next target are almost always made, even when the target is invisible. Our results demonstrate that uninterrupted on-line visual information is not necessary for accurate stepping even when (as here) each step requires visual guidance. Also, since stance prolongations did not always result, and they were always much shorter than the periods of denial, we conclude that the visuomotor control mechanism(s) are robust in the face of substantial denial of all visual information including normally preferred inputs (foveal or peripheral images) at the normally preferred times. The fact that a saccade is still made to an invisible target location implies that this is useful in itself, since it does not result in a visible foveal image. We propose that skilled, visually guided stepping onto irregularly placed targets is executed under predominantly feedforward visuomotor control mechanisms, and suggest that the ability to function effectively in this way is dependent upon the integrity of the lateral cerebellum.

Human Eye Movements During Visually Guided Stepping.

Visually guided locomotion was studied in an experiment in which human subjects (N = 8) had to accurately negotiate a series of irregularly spaced stepping-stones while infrared reflectometry and electrooculography were used to continuously record their eye movements. On average, 68% of saccades made toward the next target of footfall had been completed (visual target capture had occurred) while the foot to be positioned was still on the ground; the remainder were completed in the first 300 ms of the swing phase. The subjects' gaze remained fixed on a target, on average, until 51 ms after making contact with it, with little variation. A greater amount of variation was seen in the timing of trailing footlift relative to visual target capture. Assuming that subjects sampled the visual cues as and when they were required, visual information appeared most useful when the foot to be positioned was still on the ground.