Developmental origins of cortical hyperexcitability in Huntington's disease: Review and new observations.

Huntington's disease (HD), an inherited neurodegenerative disorder that principally affects striatum and cerebral cortex, is generally thought to have an adult onset. However, a small percentage of cases develop symptoms before 20 years of age. This juvenile variant suggests that brain development may be altered in HD. Indeed, recent evidence supports an important role of normal huntingtin during embryonic brain development and mutations in this protein cause cortical abnormalities. Functional studies also demonstrated that the cerebral cortex becomes hyperexcitable with disease progression. In this review, we examine clinical and experimental evidence that cortical development is altered in HD. We also provide preliminary evidence that cortical pyramidal neurons from R6/2 mice, a model of juvenile HD, are hyperexcitable and display dysmorphic processes as early as postnatal day 7. Further, some symptomatic mice present with anatomical abnormalities reminiscent of human focal cortical dysplasia, which could explain the occurrence of epileptic seizures in this genetic mouse model and in children with juvenile HD. Finally, we discuss recent treatments aimed at correcting abnormal brain development.

The effects of 4 weeks normobaric hypoxia training on microvascular responses in the forearm flexor.

Intermittent exposure to hypoxia can lead to improved endurance performance. Currently, it is unclear whether peripheral adaptions play a role in improving oxygen delivery and utilization following both training and detraining. This study aimed to characterize skeletal muscle blood flow (mBF), oxygen consumption (mV̇O2), and perfusion adaptations to i) 4-weeks handgrip training in hypoxic and normoxic conditions, and ii) following 4-weeks detraining. Using a randomised crossover design, 9 males completed 30-min handgrip training four times a week in hypoxic (14% FiO2 ~ 3250m altitude) and normoxic conditions. mBF, mV̇O2 and perfusion were assessed pre, post 4-weeks training, and following 4-weeks detraining. Hierarchical linear modelling found that mV̇O2 increased at a significantly faster rate (58%) with hypoxic training (0.09 mlO2·min-1 · 100g-1 per week); perfusion increased at a significantly (69%) faster rate with hypoxic training (3.72 µM per week). mBF did not significantly change for the normoxic condition, but there was a significant increase of 0.38 ml· min-1 · 100ml-1 per week (95% CI: 0.35, 0.40) for the hypoxic condition. During 4-weeks detraining, mV̇O2 and perfusion significantly declined at similar rates for both conditions, whereas mBF decreased significantly faster following hypoxic training. Four weeks hypoxic training increases the delivery and utilisation of oxygen in the periphery.

Epothilone D accelerates disease progression in the SOD1G93A mouse model of amyotrophic lateral sclerosis.

AIMS: Degeneration of the distal neuromuscular circuitry is a hallmark pathology of Amyotrophic Lateral Sclerosis (ALS). The potential for microtubule dysfunction to be a critical pathophysiological mechanism in the destruction of this circuitry is increasingly being appreciated. Stabilization of microtubules to improve neuronal integrity and pathology has been shown to be a particularly favourable approach in other neurodegenerative diseases. We present evidence here that treatment with the microtubule-targeting compound Epothilone D (EpoD) both positively and negatively affects the spinal neuromuscular circuitry in the SOD1G93A mouse model of ALS. METHODS: SOD1G93A mice were treated every 5 days with 2 mg/kg EpoD. Evaluation of motor behaviour, neurological phenotype and survival was completed, with age-dependent histological characterization also conducted, using the thy1-YFP mouse. Motor neuron degeneration, axonal integrity, neuromuscular junction (NMJ) health and gliosis were also assessed. RESULTS: EpoD treatment prevented loss of the spinal motor neuron soma, and distal axon degeneration, early in the disease course. This, however, was not associated with protection of the NMJ synapse and did not improve motor phenotype or clinical progression. EpoD administration was also found to be neurotoxic at later disease stages. This was evidenced by accelerated motor neuron cell body loss, increasing gliosis, and was associated with detrimental outcomes to motor behaviour, clinical assessment and survival. CONCLUSIONS: The results suggest that EpoD accelerates disease progression in the SOD1G93A mouse model of ALS, and highlights that the pathophysiological involvement of microtubules in ALS is an evolving and underappreciated phenomenon.

Head injury trends and helmet use in skiers and snowboarders in Western Canada, 2008-2009 to 2012-2013: an ecological study.

This research explored associations between helmet use and head injuries in snowsports by investigating reported snowsport injuries in Western Canada from 2008-2009 to 2012-2013. The key finding was that increased helmet use (from 69% to 80%) was not associated with a reduction in reported head injuries. Over the study period, the average rate of reported head injuries was 0.2/1000 skier visits, with a statistically significant variation (P < 0.001). The line of best fit showed an non-significant upward trend (P = 0.13). Lacerations were the only subcategory of head injuries that decreased significantly with helmet use. A higher proportion of people who reported a head injury were wearing a helmet than for injuries other than to the head. Skiers were more likely to report a head injury when wearing a helmet than snowboarders (P < 0.001 cf. P = 0.22). There were significant differences in characteristics of helmet and non-helmet wearers. Helmet wearers were more likely to be: young adults (P < 0.001); beginner/novices (P = 0.004); and snowboarders (P < 0.001), but helmet wearing was not associated with gender (P = 0.191). Further research is needed to explore the possible reasons for the failure of helmets to reduce head injuries, for example, increased reporting of head injuries and increased risk-taking combined with over-rating of the helmets' protection.

Haemodynamic kinetics and intermittent finger flexor performance in rock climbers.

Currently it is unclear whether blood flow (BF) or muscle oxidative capacity best governs performance during intermittent contractions to failure. The aim of this study was to determine oxygenation kinetics and BF responses during intermittent (10 s contraction: 3 s release) contractions at 40% of MVC in rock climbers of different ability (N=38). Total forearm BF, as well as de-oxygenation and re-oxygenation of the flexor digitorum profundus (FDP) and the flexor carpi radialis (FCR) were assessed. Compared to the control, intermediate and advanced groups, the elite climbers had a significantly (p<0.05) greater force time integral (FTI), MVC and MVC/kg. Furthermore, the elite climbers de-oxygenated the FDP significantly more during the first (7.8, 11.9, 12.4 vs. 15.7 O2%) and middle (7.3, 8.8, 10.4 vs.15.3 O2%) phases of contractions as well as for the FCR during the first phase only (8.3, 7, 11.7 vs. 13.3 O2%). They also had a significantly higher BF upon release of the contractions (656, 701, 764 vs. 971 mL ∙ min(-1)). The higher FTI seen in elite climbers may be attributable to a greater blood delivery, and an enhanced O2 recovery during the 3 s release periods, as well as a superior muscle oxidative capacity associated with the greater de-oxygenation during the 10 s contractions.

A psychophysiological comparison of on-sight lead and top rope ascents in advanced rock climbers.

Research suggests that lead climbing is both physiologically and psychologically more stressful than top rope climbing for intermediate performers. This observation may not be true for advanced climbers, who train regularly on lead routes and are accustomed to leader falls. The aim of this study was to compare the psychophysiological stresses of lead and top rope on-sight ascents in advanced rock climbers. Twenty-one climbers (18 men and three women) ascended routes near or at the best of their ability (22 Ewbank). Psychological stress was measured preclimb using the Revised Comparative State Anxiety Inventory (CSAI-2R). Plasma cortisol was sampled at six intervals. The volume of oxygen (VO2 ) and heart rate (Hr) were measured throughout the climbs. No significant differences were found in self-confidence, somatic, or cognitive anxiety between the conditions lead and top rope. No significant differences in plasma cortisol concentration were found between any time points. No significant relationships were found between cortisol and any CSAI-2R measures. No significant differences were found between conditions for VO2 or blood lactate concentration. During the lead climb, Hr was significantly elevated during the last part of the route. Findings suggest that advanced rock climbers do not find lead climbing to be more stressful than top rope climbing during an on-sight ascent.

Telemedicine in Neurology: Challenges and Opportunities.

Objective: Our objective is to explore challenges encountered by neurologists with the use of telemedicine in neurology. Methods: A cross- sectional study via an anonymous survey to explore neurologists' experiences with telemedicine. They survey was sent to randomly selected 200 participants from Academic Institutions in the United States. Descriptive statistics were reported as percentages for each survey question. Results: 110 neurologists completed the survey. Fifty-one percent of neurologists stated that they experienced technological issues in (1%-20%) of telemedicine visits and 57% of neurologists needed technological assistance from informational technology support. With regards to the impact of limited neurological examination via telemedicine, 34% of neurologists agreed that the limited examination makes them worried that they are providing a suboptimal care to patients and 55% recommended a subsequent in-person visit (in 1%-20% of telemedicine visits) for further evaluation. Among the challenges that hindered patients' ability to participate in telemedicine visits, 95% of neurologists rated patients' technological challenges with setting up telemedicine to be the most common issue encountered, 37% of neurologists rated patient's cognitive/mental disability to be the second most common challenge to complete telemedicine visits as well as availability of interpreter services for non-English speaking patients. Neurologists rated improving administrative support (39%), integration of EMR for video and telephone calls (37%), and sufficient time allotment to complete telemedicine visits (27%) to be the most important issues to address to optimize the use of telemedicine in neurology. Significance: Potential opportunities to improve neurologists' experiences in telemedicine include improving technological support, integration of virtual platforms within the EMR, and adequate administrative support. Patients with cognitive/physical disabilities may need additional support to engage in the health system via telemedicine.

Plasma cortisol concentrations and perceived anxiety in response to on-sight rock climbing.

Previous research suggested plasma cortisol concentrations in response to rock climbing have a cubic relationship with state anxiety and self-confidence. This research, however, was conducted in a situation where the climbers had previously climbed the route. The purpose of our study was to examine this relationship in response to on-sight climbing. Nineteen (13 male, 6 female) intermediate climbers volunteered to attend anthropometric and baseline testing sessions, prior to an on-sight ascent (lead climb or top-rope) of the test climb (grade 19 Ewbank/6a sport/5.10b YDS). Data recorded included state anxiety, self-confidence and cortisol concentrations prior to completing the climb. Results indicated that there were no significant differences in state anxiety, self-confidence and plasma cortisol concentration regardless of the style of ascent (lead climb or top-rope) in an on-sight sport climbing context. Regression analysis indicated there was a significant linear relationship between plasma cortisol concentrations and self-confidence (r= - 0.52, R2=0.267, p=0.024), cognitive (r=0.5, R2=0.253, p=0.028), and somatic anxieties (r=0.46, R2=0.210, p=0.049). In an on-sight condition the relationships between plasma cortisol concentrations with anxiety (cognitive and somatic) and self-confidence were linear.

Capillary cortisol sampling during high-intensity exercise.

Venepuncture is the established "gold standard" for sampling cortisol, but it is expensive, highly invasive and impractical for many experimental and clinical settings. Salivary free cortisol is a non-invasive and practical alternative; however, when cortisol concentrations exceed 500 nmol · L there is a lack of agreement between salivary (free) and venous (bound) cortisol. No known research has assessed whether capillary cortisol accurately reflects venous blood cortisol across a range of concentrations. The objective of the current study was to determine the agreement between capillary and venous blood samples of total plasma cortisol across a range of concentrations. 11 healthy male subjects (26.1 ± 5.3 years) were recruited. Capillary and venous blood samples were collected pre and post (immediately post and post 5, 10, 15 and 20 min) a treadmill VO2max test. Regression analysis revealed a strong relationship (R2=0.96, y=1.0028x + 1.2964 (P<0.05)) between capillary and venous cortisol concentrations. A Bland-Altman plot showed all data was within the upper and lower bounds of the 95% confidence interval, and no systematic bias was evident. In conclusion, capillary sampling is a valid technique for measuring bound cortisol across a range of concentrations.

Comparison of plasma cortisol sampling sites for rock climbing.

AIM: Blood samples for the determination of plasma cortisol concentration are generally obtained via venipuncture or capillary sampling at the fingertip. During rock climbing the upper body, forearms and fingertips are subject to continual loading and gripping making sampling at these sites problematic. The purpose of this study was to examine differences in plasma cortisol concentrations from capillary samples taken at the fingertip and first (big) toe in a rock climbing context. METHODS: Nine (8 males, 1 female) climbers completed a succession of climbing bouts at three different angles (91°,100° and 110°). Capillary blood samples were taken simultaneously from the fingertip and first toe pre and post climb at each angle. Plasma samples were collected via centrifugation and subsequently analysed for cortisol using an Enzyme-Linked Immunosorbent Assay (ELISA) kit. All standards and samples were analysed in duplicate. Intra assay coeffiecients of variation (CV%) were 5.91% and 7.94% for finger and toe respectively. RESULTS: A limits of agreement plot revealed all data points to be well within upper and lower bounds of the 95% population confidence interval. Paired samples t-tests (for finger and toe) indicated there were no significant differences between sample sites. Subsequent regression analysis revealed a strong relationship (R2=0.78, y=1.031x - 2.079) between fingertip and first toe capillary plasma cortisol concentrations. CONCLUSION: Findings suggest that the first toe offers a valid alternative sampling site for plasma cortisol concentration in a rock climbing context.

Comparison of lactate sampling sites for rock climbing.

Comparisons of capillary blood lactate concentrations pre and post climb have featured in the protocols of many rock climbing studies, with most researchers obtaining samples from the fingertip. The nature of rock climbing, however, places a comparatively high physiological loading on the foreaand fingertips. Indeed, the fingertips are continually required for gripping and this makes pre-climb sampling at this site problematic. The purpose of our study was to examine differences in capillary blood lactate concentrations from samples taken at the fingertip and first (big) toe in a rock climbing context. 10 participants (9 males and 1 female) completed climbing bouts at 3 different angles (91°, 100° and 110°). Capillary blood samples were taken simultaneously from the fingertip and first toe pre and post climb. A limit of agreement plot revealed all data points to be well within the upper and lower bounds of the 95% population confidence interval. Subsequent regression analysis revealed a strong relationship (R (2)=0.94, y=0.940x + 0.208) between fingertip and first toe capillary blood lactate concentrations. Findings from our study suggest that the toe offers a valid alternative site for capillary blood lactate concentration analysis in a rock climbing context.

Sport-specific power assessment for rock climbing.

AIM: The popularity of rock climbing has resulted in a growing research base for the sport. However, at present there is a lack of sport-specific measures of performance in the field. The aim of this study was to examine the use of the powerslap test as a sport specific power measure. METHODS: The participants in this study were categorised into four different ability groups (novice, intermediate, advanced and elite) based on self reported lead grade. Two separate experiments were conducted to determine validity and reliability. The powerslap test was conducted on a revolution board with two variations - wide and narrow grip, for both sides of the body. The test started with the climber hanging at full extension from two holds from which a pull up movement was made releasing one hand to slap a scaled score board above. RESULTS: There was a significant relationship between powerslap scores and climbing ability (Left Wide: r=0.7, P<0.0005; right wide: r=0.69, P<0.0005; left narrow: r=0.73, P<0.0005; right narrow: r =0.72, P<0.0005). Further to this, scores on the powerslap narrow test were significantly differentiated by climber ability (LEFT: F(3,37)=15.74, P<0.0005; right: F(3,37)=12.16, P<0.0005). Limits of agreement and intra-class correlation indicated that the powerslap test is a reliable performance measure. CONCLUSION: According to the present findings the narrow grip variation of the powerslap test is a useful sport-specific power test that is related to climbing performance.

Walking for fitness: is it enough to maintain both heart and bone health?

Exercising at levels of whole body accelerations exceeding 3.6g has been shown to have positive effects on cardiovascular fitness, bone density and balance. This pilot research project evaluated the whole body accelerations and cardiovascular challenge provided by selected walks in the Canberra region of Australia to determine if walks could be ranked according to potential level of impact on both cardiovascular fitness and bone health. Nine participants, who described themselves as walking at least 3km, three times per week, wore a data logging device recording heart rate, acceleration and GPS position while walking three outdoor tracks: (1) the running track of an athletics stadium; (2) on a hill climb path through bushland; and (3) on a route through suburban streets. There was a significant difference (P<0.05) for heart rate, distribution of whole body accelerations and average walking speed between track 2 and tracks 1 and 3. There was a significant difference for heart rate, distribution of whole body accelerations and average walking speed between the walks. The running track and the suburban walk provide a moderate exercise challenge, with the hill climb walk providing progressively greater vertical height challenge, resulting in an increased cardiovascular exercise challenge. No participant effectively exceeded the threshold for achieving a positive impact on bone density (100 or more accelerations/day >3.6g) on track 1, and only two of the nine participants intermittently achieved this threshold on tracks 2 and 3.

Epothilone D alters normal growth, viability and microtubule dependent intracellular functions of cortical neurons in vitro.

Brain penetrant microtubule stabilising agents (MSAs) are being increasingly validated as potential therapeutic strategies for neurodegenerative diseases and traumatic injuries of the nervous system. MSAs are historically used to treat malignancies to great effect. However, this treatment strategy can also cause adverse off-target impacts, such as the generation of debilitating neuropathy and axonal loss. Understanding of the effects that individual MSAs have on neurons of the central nervous system is still incomplete. Previous research has revealed that aberrant microtubule stabilisation can perturb many neuronal functions, such as neuronal polarity, neurite outgrowth, microtubule dependant transport and overall neuronal viability. In the current study, we evaluate the dose dependant impact of epothilone D, a brain penetrant MSA, on both immature and relatively mature mouse cortical neurons in vitro. We show that epothilone D reduces the viability, growth and complexity of immature cortical neurons in a dose dependant manner. Furthermore, in relatively mature cortical neurons, we demonstrate that while cellularly lethal doses of epothilone D cause cellular demise, low sub lethal doses can also affect mitochondrial transport over time. Our results reveal an underappreciated mitochondrial disruption over a wide range of epothilone D doses and reiterate the importance of understanding the dosage, timing and intended outcome of MSAs, with particular emphasis on brain penetrant MSAs being considered to target neurons in disease and trauma.

Nutrients cause grassland biomass to outpace herbivory.

Human activities are transforming grassland biomass via changing climate, elemental nutrients, and herbivory. Theory predicts that food-limited herbivores will consume any additional biomass stimulated by nutrient inputs ('consumer-controlled'). Alternatively, nutrient supply is predicted to increase biomass where herbivores alter community composition or are limited by factors other than food ('resource-controlled'). Using an experiment replicated in 58 grasslands spanning six continents, we show that nutrient addition and vertebrate herbivore exclusion each caused sustained increases in aboveground live biomass over a decade, but consumer control was weak. However, at sites with high vertebrate grazing intensity or domestic livestock, herbivores consumed the additional fertilization-induced biomass, supporting the consumer-controlled prediction. Herbivores most effectively reduced the additional live biomass at sites with low precipitation or high ambient soil nitrogen. Overall, these experimental results suggest that grassland biomass will outstrip wild herbivore control as human activities increase elemental nutrient supply, with widespread consequences for grazing and fire risk.

Bis(7)-tacrine, a promising anti-Alzheimer's dimer, affords dose- and time-dependent neuroprotection against transient focal cerebral ischemia.

Bis(7)-tacrine, a promising anti-Alzheimer's dimer, has been shown to have multiple neuroprotective activities in vitro. Here, we investigate whether bis(7)-tacrine attenuates focal cerebral ischemic impairment in vivo. Cerebral ischemia was induced in Sprague-Dawley rats by transient (2h) middle cerebral artery occlusion (MCAO) followed by 24h of reperfusion. Bis(7)-tacrine administered intraperitoneally 15 min after ischemia dose-dependently improved neurological behavior deficits and reduced both cerebral infarct volume and edema. The TUNEL staining assay showed that bis(7)-tacrine attenuated neuronal apoptosis in the penumbral region. Compared with that for memantine, a moderately effective N-methyl-d-aspartate (NMDA) receptor antagonist with a similar affinity and potency to bis(7)-tacrine in blocking NMDA receptors, the therapeutic window for bis(7)-tacrine was wider and lasted up to 6h after the onset of ischemia. Bis(7)-tacrine did not affect physiological parameters or regional cerebral blood flow during either the occlusion period or the early reperfusion stage. In conclusion, bis(7)-tacrine dose- and time-dependently protected against acute focal cerebral ischemic insults, possibly through the drug's anti-apoptotic effects during multiple events in the ischemic cascade.

Does group B streptococcal infection contribute significantly to neonatal sepsis in Antigua and Barbuda?

Group B streptococcus is the most common cause of neonatal sepsis in the United States of America (USA). This study was undertaken to determine the contribution of group B streptococcus to neonatal septicaemia in Antigua and Barbuda. From 1994 to 2002, there were about 12,000 births, with 2500 Special Care Nursery admissions, 1100 (44%) with potential neonatal septicaemia. Blood cultures were done in 433/1100 (39%) and cerebrospinal fluid cultures in 52/1100 (5%). Positive cultures were seen in 41/433 (9.5%) with group B streptococcus in 1/41 (2.4%), streptococcus "species" in 3/41 (7.4%) and positive cerebrospinal fluid cultures were seen in 2/52 (one group B streptococcus) giving 5 per 12,000 or 0.4 cases per 1000 babies. Vaginal cultures from 1994 to 2002 revealed group B streptococcus in 14/163 (8.6%) of positive bacterial cultures. A sample of pregnant women from a private office had positive culture for group B streptococcus in 2/120 (1.7%). The prevalence rate of carriage (15 to 40%) and infection (1.7 to 4 per 1000 babies) was much higher in the USA in the same period Universal screening of mothers for group B streptococcus may not be as necessary or cost-effective in Antigua and Barbuda.

Differences in forearm strength, endurance, and hemodynamic kinetics between male boulderers and lead rock climbers.

This study examined differences in the oxygenation kinetics and strength and endurance characteristics of boulderers and lead sport climbers. Using near infrared spectroscopy, 13-boulderers, 10-lead climbers, and 10-controls completed assessments of oxidative capacity index and muscle oxygen consumption (m⩒O2) in the flexor digitorum profundus (FDP), and extensor digitorum communis (EDC). Additionally, forearm strength (maximal volitional contraction MVC), endurance (force-time integral FTI at 40% MVC), and forearm volume (FAV and ΔFAV) was assessed. MVC was significantly greater in boulderers compared to lead climbers (mean difference = 9.6, 95% CI 5.2-14 kg). FDP and EDC oxidative capacity indexes were significantly greater (p = .041 and .013, respectively) in lead climbers and boulderers compared to controls (mean difference = -1.166, 95% CI (-3.264 to 0.931 s) and mean difference = -1.120, 95% CI (-3.316 to 1.075 s), respectively) with no differences between climbing disciplines. Climbers had a significantly greater FTI compared to controls (mean difference = 2205, 95% CI= 1114-3296 and mean difference = 1716, 95% CI = 553-2880, respectively) but not between disciplines. There were no significant group differences in ΔFAV or m⩒O2. The greater MVC in boulderers may be due to neural adaptation and not hypertrophy. A greater oxidative capacity index in both climbing groups suggests that irrespective of climbing discipline, trainers, coaches, and practitioners should consider forearm specific aerobic training to aid performance.

Localization of glutamate receptors in developing cortical neurons in culture and relationship to susceptibility to excitotoxicity.

Overactivation of glutamate receptors leading to excitotoxicity has been implicated in the neurodegenerative alterations of a range of central nervous system (CNS) disorders. We have investigated the cell-type-specific changes in glutamate receptor localization in developing cortical neurons in culture, as well as the relationship between glutamate receptor subunit distribution with synapse formation and susceptibility to excitotoxicity. Glutamate receptor subunit clustering was present prior to the formation of synapses. However, different receptor types showed distinctive temporal patterns of subunit clustering, localization to spines, and apposition to presynaptic terminals. N-methyl-D-aspartate (NMDA) receptor subunit immunolabelling was present in puncta along dendrites prior to the formation of synapses, with relatively little localization to spines. Vulnerability to NMDA receptor-mediated excitotoxicity occurred before receptor subunits became localized in apposition to presynaptic terminals. Clustering of alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) receptors occurred concurrently with development of vulnerability to excitotoxicity and was related to localization of AMPA receptors at synapses and in spines. Different AMPA receptor subunits demonstrated cell-type-specific localization as well as distribution to spines, dendrites, and extrasynaptic subunit clusters. A subclass of neurons demonstrated substantial perineuronal synaptic innervation, and these neurons expressed relatively high levels of GluR1 and/or GluR4 at receptor puncta, indicating the presence of calcium-permeable AMPA receptors and suggesting alternative synaptic signalling mechanisms and vulnerability to excitotoxicity. These data demonstrate the relationship between glutamate receptor subunit expression and localization with synaptogenesis and development of neuronal susceptibility to excitotoxicity. These data also suggest that excitotoxicity can be mediated through extrasynaptic receptor subunit complexes along dendrites.