Dissociable roles of thalamic nuclei in the refinement of reaches to spatial targets.

Reaches are complex movements that are critical for survival, and encompass the control of different aspects such as direction, speed, and endpoint precision. Complex movements have been postulated to be learned and controlled through distributed motor networks, of which the thalamus is a highly connected node. Still, the role of different thalamic circuits in learning and controlling specific aspects of reaches has not been investigated. We report dissociable roles of two distinct thalamic nuclei - the parafascicular (Pf) and ventroanterior/ventrolateral (VAL) nuclei - in the refinement of spatial target reaches in mice. Using 2-photon calcium imaging in a head-fixed joystick task where mice learned to reach to a target in space, we found that glutamatergic neurons in both areas were most active during reaches early in learning. Reach-related activity in both areas decreased late in learning, as movement direction was refined and reaches increased in accuracy. Furthermore, the population dynamics of Pf, but not VAL, covaried in different subspaces in early and late learning, but eventually stabilized in late learning. The neural activity in Pf, but not VAL, encoded the direction of reaches in early but not late learning. Accordingly, bilateral lesions of Pf before, but not after learning, strongly and specifically impaired the refinement of reach direction. VAL lesions did not impact direction refinement, but instead resulted in increased speed and target overshoot. Our findings provide new evidence that the thalamus is a critical motor node in the learning and control of reaching movements, with specific subnuclei controlling distinct aspects of the reach early in learning.

Exploration biases how forelimb reaches to a spatial target are learned.

The brain can learn to generate actions, such as reaching to a target, using different movement strategies. Understanding how different variables bias which strategies are learned to produce such a reach is important for our understanding of the neural bases of movement. Here we introduce a novel spatial forelimb target task in which perched head-fixed mice learn to reach to a circular target area from a set start position using a joystick. These reaches can be achieved by learning to move into a specific direction or to a specific endpoint location. We find that mice gradually learn to successfully reach the covert target. With time, they refine their initially exploratory complex joystick trajectories into controlled targeted reaches. The execution of these controlled reaches depends on the sensorimotor cortex. Using a probe test with shifting start positions, we show that individual mice learned to use strategies biased to either direction or endpoint-based movements. The degree of endpoint learning bias was correlated with the spatial directional variability with which the workspace was explored early in training. Furthermore, we demonstrate that reinforcement learning model agents exhibit a similar correlation between directional variability during training and learned strategy. These results provide evidence that individual exploratory behavior during training biases the control strategies that mice use to perform forelimb covert target reaches.

The effect of supplementing pony diets with yeast on 1. In vivo and in vitro digestibility, faecal pH and particle size.

Fibre is essential to maintain healthy gut; however, energy demands of performance horses can be too high to be met by forages alone. Yeast may support the function of cellulolytic bacteria to digest fibre. The aim of this work was to determine the effect of an oral supplement (VistaEQ) containing 4% live yeast on the in vitro and in vivo digestibility of high-starch (HS) and high-fibre diets (HF). Eight ponies were used in a 4 × 4 Latin square design consisting of 4- × 19-day periods and four diets: HF, HF + yeast (HFY), HS and HS + yeast (HSY). In vivo apparent digestibility (AD) was estimated using total collection technique, and faecal particle size was measured using NASCO digestive analyser. Faeces from the ponies were subsequently used as an inoculum in ANKOM RF gas production system to assess fermentation kinetics in vitro. Each module contained 1 g of feed substrate DM in the following combinations: 50% grass hay and 50% alfalfa (HF_50 : 50) or concentrate (HS_50 : 50), and 75% grass hay and 25% alfalfa (HF_75 : 25) or concentrate (HS_75 : 25) with or without yeast. Yeast was able to induce more gas production from HF_75 : 25, HS_75 : 25 and HF_50 : 50 feed substrates incubated with respective faecal inoculum base. Yeast did not affect pH in vitro when the substrates were incubated in 50 : 50 ratio, while the pH was higher for HF_75 : 25 incubated with correspondent faecal inoculum compared to HS_75 : 25 and HSY_75 : 25. Yeast had no effects on ADF and CP AD of either diet. Yeast addition increased DM (HF: 0.2%, HS: 0.4%), organic matter (HF: 0.7%, HS: 1.3%), NDF (HF: 0.5%, HS: 1.5%), total detergent fibre (HF: 0.7%; HS: 0.4%) (P < 0.05) and also tended to increase hemicellulose AD (HF: 0.9%, HS: 1.2%) (P < 0.10). Faecal pH in vivo was higher for both HF diets compared to HS diet without yeast supplementation (P < 0.001, HF and HFY: 6.8; HS: 6.6, HSY: 6.7). However, no difference was observed in faecal pH when HSY was compared to both HF diets. Yeast had no effect on the size of the faecal particles (P > 0.05). Yeast increased in vitro gas production, suggesting more energy could be extracted from the feed, and the in vivo AD of some of the nutrients when HF and HS diets were fed.

The effect of supplementing pony diets with yeast on 2. The faecal microbiome.

There is a need to develop feeding strategies to prevent the adverse effect of concentrate feeding in high-performance horses fed energy-dense diets aiming to maintain their health and welfare. The objective of this study is to determine the effect of a VistaEQ product containing 4% live yeast Saccharomyces cerevisiae (S. cerevisiae), with activity 5 × 108 colony-forming unit/g and fed 2 g/pony per day, on faecal microbial populations when supplemented with high-starch and high-fibre diets using Illumina next generation sequencing of the V3-V4 region of the 16S ribosomal RNA gene. The four treatments were allocated to eight mature Welsh section A pony geldings enrolled in a 4-period × 8 animal crossover design. Each 19-day experimental period consisted of an 18-day adaptation phase and a single collection day, followed by a 7-day wash out period. After DNA extraction from faeces and library preparation, α-diversity and linear discriminant analysis effect size were performed using 16S metagenomics pipeline in Quantitative Insights Into Microbial Ecology (QIIME™) and Galaxy/Hutlab. Differences between the groups were considered significant when linear discriminant analysis score was >2 corresponding to P < 0.05. The present study showed that S. cerevisiae used was able to induce positive changes in the equine microbiota when supplemented to a high-fibre diet: it increased relative abundance (RA) of Lachnospiraceae and Dehalobacteriaceae family members associated with a healthy core microbiome. Yeast supplementation also increased the RA of fibrolytic bacteria (Ruminococcus) when fed with a high-fibre diet and reduced the RA of lactate producing bacteria (Streptococcus) when a high-starch diet was fed. In addition, yeast increased the RA of acetic, succinic acid producing bacterial family (Succinivibrionaceae) and butyrate producing bacterial genus (Roseburia) when fed with high-starch and high-fibre diets, respectively. VistaEQ supplementation to equine diets can be potentially used to prevent acidosis and increase fibre digestibility. It may help to meet the energy requirements of performance horses while maintaining gut health.

Equine dietary supplements: an insight into their use and perceptions in the Irish equine industry.

BACKGROUND: Nutritional supplements are frequently used by horse owners/caregivers to supplement their horse(s) diets. Some work has been done to identify the types of supplements fed and the reasons for doing so; however, this has been predominantly disciple-specific and with little focus on participants' perceptions of supplement testing and regulation. The aim of this study was to gain an insight into the use and perceptions of equine dietary supplements in the Irish equestrian industry. METHODS: An online survey was designed to ascertain the following information: demographics, types of supplements fed and reasons for use, factors that influenced respondents' choice of supplement, where advice was sought and perceptions of testing and regulation of equine supplements. RESULTS: The survey yielded 134 responses, 70% non-professionals and 30% professionals. A greater percentage of professionals included supplements in their horse(s) diets (98%) compared to non-professionals (86%). Almost 70% of professionals fed more than two supplements, whereas 80% of non-professionals reported to feed only one supplement. Joint supplements were most commonly fed by all respondents (22%) followed by calming supplements (13%). The enhancement of performance (35%) and prevention of joint disorders (34%) were the most common reasons reported by respondents for using a supplement. Over 53% of respondents sought advice on choosing a supplement from their feed merchant, followed by their veterinarian (46%). Veterinary recommendation was given as the most influential factor when choosing a supplement by 90% of respondents, followed by cost (69%). Most (93%) respondents thought that feed supplements had to meet legal standards, with each batch analysed for quality (72%) and the supplement tested on horses before being launched on to the market (92%). CONCLUSION: This study has identified the main types of supplements used in the Irish equestrian industry along with the reasons for their use. However, it has also highlighted major misperceptions in how supplements are tested before being launched for sale and further work on this aspect of the findings would be beneficial.

Assessing the impacts of bait collection on inter-tidal sediment and the associated macrofaunal and bird communities: The importance of appropriate spatial scales.

Bait collection is a multibillion dollar worldwide activity that is often managed ineffectively. For managers to understand the impacts on protected inter-tidal mudflats and waders at appropriate spatial scales macrofaunal surveys combined with video recordings of birds and bait collectors were undertaken at two UK sites. Dug sediment constituted approximately 8% of the surveyed area at both sites and is less muddy (lower organic content) than undug sediment. This may have significant implications for turbidity. Differences in the macrofaunal community between dug and undug areas if the same shore height is compared as well as changes in the dispersion of the community occurred at one site. Collection also induces a 'temporary loss of habitat' for some birds as bait collector numbers negatively correlate with wader and gull abundance. Bait collection changes the coherence and ecological structure of inter-tidal mudflats as well as directly affecting wading birds. However, as ß diversity increased we suggest that management at appropriate hectare/site scales could maximise biodiversity/function whilst still supporting collection.

Characterization of hepatitis B virus surface antigen variability and impact on HBs antigen clearance under nucleos(t)ide analogue therapy.

For hepatitis B virus (HBV)-related chronic infection under treatment by nucleos(t)ide analogues (NUCs), HBsAg clearance is the ultimate therapeutic goal but very infrequent. We investigated how HBV envelope protein variability could lead to differential HBsAg clearance on NUCs. For 12 HBV genotype D patients receiving NUCs, six resolvers (HBsAg clearance) were compared to six matched nonresolvers (HBsAg persistence). PreS/S amino acid (aa) sequences were analysed with bioinformatics to predict HBV envelope antigenicity and aa covariance. To enrich our analyses on very rare resolvers, these were compared with other HBV genotype D strains in three characterized clinical cohorts including common chronically infected patients. The sT125M+sP127T combination was observed in four nonresolvers of six, corroborated by aa covariance analysis, associated with a lower predicted antigenicity than sT125T+sP127P. Concordant features within this HBV key functional domain, at positions 125 and 127, were reported from two of the three comparative cohorts. In our hands, a lower ELISA reactivity of HBV-vaccinated mice sera was observed against the sT125M mutant. In the S gene, 56 aa changes in minor variants were detected in non-resolvers, mainly in the major hydrophilic region, vs 28 aa changes in resolvers. Molecular features in patients showing HBsAg persistence on NUCs argue in favour of a different aa pattern in the HBV S gene compared to those showing HBsAg clearance. In nonresolvers, a decrease in HBs 'a' determinant antigenicity and more frequent mutations in the S gene suggest a role for the HBV envelope characteristics in HBsAg persistence.

More bang for your monitoring bucks: Detection and reporting of non-indigenous species.

'Collect once, use often' is a frequently cited principle in both national and international efforts to promote the collection, archiving and sharing of marine monitoring data. Since the implementation of the Marine Conservation Zone (MCZ) evidence collection programme, 67 recommended MCZ sites have been visited and a suite of marine data collected. Here we present how this dataset was utilised outside of the MCZ programme to identify occurrences of non-indigenous species (NIS) around the UK coast. One hundred and thirty-five aquatic species from the Non-native Species Information Portal (NNSIP) register were used to produce a standard list of NIS against which, infauna and epifaunal data records from the MCZ project were compared. A total of 20 NIS were identified across 42 of the 67 sites surveyed. This study demonstrates that with sufficient coordination and management data collected for other purposes can be easily utilised to address additional policy requirements.

The conserved Fanconi anemia nuclease Fan1 and the SUMO E3 ligase Pli1 act in two novel Pso2-independent pathways of DNA interstrand crosslink repair in yeast.

DNA interstrand cross-links (ICLs) represent a physical barrier to the progression of cellular machinery involved in DNA metabolism. Thus, this type of adduct represents a serious threat to genomic stability and as such, several DNA repair pathways have evolved in both higher and lower eukaryotes to identify this type of damage and restore the integrity of the genetic material. Human cells possess a specialized ICL-repair system, the Fanconi anemia (FA) pathway. Conversely yeasts rely on the concerted action of several DNA repair systems. Recent work in higher eukaryotes identified and characterized a novel conserved FA component, FAN1 (Fanconi anemia-associated nuclease 1, or FANCD2/FANCI-associated nuclease 1). In this study, we characterize Fan1 in the yeast Schizosaccharomyces pombe. Using standard genetics, we demonstrate that Fan1 is a key component of a previously unidentified ICL-resolution pathway. Using high-throughput synthetic genetic arrays, we also demonstrate the existence of a third pathway of ICL repair, dependent on the SUMO E3 ligase Pli1. Finally, using sequence-threaded homology models, we predict and validate key residues essential for Fan1 activity in ICL repair.

Turing patterns from dynamics of early HIV infection.

We have developed a mathematical model for in-host virus dynamics that includes spatial chemotaxis and diffusion across a two-dimensional surface representing the vaginal or rectal epithelium at primary HIV infection. A linear stability analysis of the steady state solutions identified conditions for Turing instability pattern formation. We have solved the model equations numerically using parameter values obtained from previous experimental results for HIV infections. Simulations of the model for this surface show hot spots of infection. Understanding this localization is an important step in the ability to correctly model early HIV infection. These spatial variations also have implications for the development and effectiveness of microbicides against HIV.

Periarticular local anesthesia does not improve pain or mobility after THA.

BACKGROUND: Periarticular infiltration of local anesthetic, NSAIDs, and adrenaline have been reported to reduce postoperative pain, improve mobility, and reduce hospital stay for patients having THAs, but available studies have not determined whether local anesthetic infiltration alone achieves similar improvements. QUESTIONS: We therefore asked whether periarticular injection of a local anesthetic during THA reduced postoperative pain and opioid requirements and improved postoperative mobility. METHODS: We randomized 96 patients to either treatment (n = 50) or control groups (n = 46). Before wound closure, the treatment group received local infiltration of 160 mL of levobupivacaine with adrenaline. The control group received no local infiltration. We assessed postoperative morphine consumption and pain during the 24 hours after surgery. Mobilization was assessed 24 hours postoperatively with supine-to-sit and sit-to-stand transfers, timed 10-m walk test, and timed stair ascent and descent. Patients and assessing physiotherapists were blind to study status. RESULT: We observed no differences in postoperative morphine consumption, time to ascend and descend stairs, or ability to transfer between treatment and control groups. The treatment group reported more pain 7 to 12 hours postoperatively, but there were no differences in pain scores between groups at all other postoperative intervals. The treatment group showed increased postoperative walking speed greater than 6 m, but not greater than 10 m, compared with the control group. CONCLUSIONS: Periarticular infiltration of local anesthetic during THA did not reduce postoperative pain or length of hospital stay and did not improve early postoperative mobilization.

A screening algorithm for HIV-associated neurocognitive disorders.

BACKGROUND: HIV physicians have limited time for cognitive screening. Here we developed an extra-brief, clinically based tool for predicting HIV-associated neurocognitive impairment (HAND) in order to determine which HIV-positive individuals require a more comprehensive neurological/neuropsychological (NP) assessment. METHODS: Ninety-seven HIV-positive individuals with advanced disease recruited in an HIV out-patient clinic received standard NP testing. A screening algorithm was developed using support vector machines, an optimized prediction procedure for classifying individuals into two groups (here NP-impaired and NP-normal) based on a set of predictors. RESULTS: The final algorithm utilized age, current CD4 cell count, past central nervous system HIV-related diseases and current treatment duration and required approximately 3 min to complete, with a good overall prediction accuracy of 78% (against the gold standard; NP-impairment status derived from standard NP testing) and a good specificity of 70%. CONCLUSION: This noncognitive-based algorithm should prove useful to identify HIV-infected patients with advanced disease at high risk of HAND who require more formal assessment. We propose staged guidelines, using the algorithm, for improved HAND therapeutic management. Future larger, international studies are planned to test the predictive effect of nadir CD4 cell count, hepatitis C virus infection, gender, ethnicity and HIV viral clade. We recommend the use of this first version for HIV-infected Caucasian men with advanced disease.

Lower limb blocks.

The advances in regional techniques for blocks of the lower limb have been driven primarily by the need to produce effective analgesia in the postoperative period and beyond. These techniques are commonly performed before or after central neuraxial blockade when this technique is used to provide anaesthesia and analgesia for the surgical procedure. Increasingly, modern practice demands a shorter hospital stay, improved patient expectations and early mobilisation. This article describes the current methods and reasons for performing specific blocks to the lower limb and the management of these blocks particularly in the postoperative period.

Post-operative anaemia in femoral neck fracture patients: does it need treatment? A single blinded prospective randomised controlled trial.

A prospective randomised controlled trial was performed to establish the effect of oral iron supplementation on haemoglobin level at 4 weeks post-operative in elderly patients with fractured neck of femur undergoing surgical treatment. We single blindly randomised 68 patients into two groups. Thirty-four patients in the treatment group were compared with 32 in the control group. The treatment group received 200mg of oral iron tablets 3 times a day for 4 weeks in the post-operative period compared to nothing for the control group. The groups were comparable in all other aspects. The iron treatment resulted in significantly increased haemoglobin value at 4 weeks; 0.76 g% higher than the control group (95% CI of +0.01 to +1.51) which is statistically significant (P<0.05). There was no major complication. We recommend oral iron supplementation in elderly anaemic patients with hip fracture in the post-operative period.

Secondary prevention of fragility fractures: are we following the guidelines? Closing the audit loop.

INTRODUCTION: The aim of this study was to determine whether orthopaedic surgeons follow the British Orthopaedic Association (BOA) guidelines for secondary prevention of fragility fractures. PATIENTS AND METHODS: A retrospective audit was conducted on patients with neck of femur fractures treated in our hospital between October and November 2003. A re-audit was conducted during the period August to October 2004. RESULTS: There were 27 patients in the initial study period. Twenty-six patients (96%)had full blood count measured with LFT and bone-profile measured in 18 patients (66%). Only nine patients (30%)had treatment for osteoporosis (calcium and vitamin D). Only one patient was referred for DEXA scan. Steps were taken in the form of creating better awareness among the junior doctors and nurse practitioners of the BOA guidelines. In patients above 80 years of age, it was decided to use abbreviated mental score above 7 as a clinical criteria for DEXA referral. A hospital protocol based on BOA guidelines was made. A re-audit was conducted during the period August to October 2004. There were 37 patients. All had their full blood count and renal profile checked (100%). The bone-profile was measured in 28 (75.7%) and LFT in 34 (91.9%) patients. Twenty-four patients (65%) received treatment in the form of calcium + vitamin D (20) and bisphosphonate (4). DEXA-scan referral was not indicated in 14 patients as 4 were already on bisphosphonates and for 10 patients their abbreviated mental score was less than 7. Among the remaining 23 patients, 9 patients (40%) were referred for DEXA scan. This improvement is statistically significant (P = 0.03, chi square test). DISCUSSION AND CONCLUSIONS: The re-audit shows that, although there is an improvement in the situation, we are still below the standards of secondary prevention of fragility fractures with 60% of femoral fragility fracture patients not being referred for DEXA scan. A pathway lead by a fracture liaison nurse dedicated to osteoporotic fracture patients should improve the situation.

A common aberration with water-immersion objective lenses.

We describe here an aberration that is frequently encountered with water-immersion but not oil-immersion objectives. The aberration is shown to be induced by tilt of the coverslip out of the plane normal to the optical axis. Model calculations taking into account the path-length distortions introduced by a tilted coverslip satisfactorily reproduce the observed effect on the images of small subresolution fluorescent beads.

The effect of heterogeneity on optimal regimens in cancer chemotherapy.

Optimal drug regimens for cancer chemotherapy are determined when knowledge is only available on the behaviour of the tumour and the drugs used, over a population of patients. The case of two drugs is investigated where they are equivalent on average. Our calculations indicate that the optimal regimen has both drugs given initially but then sequences the two drugs. Our calculations also indicate that as tumour heterogeneity increases, the benefit to be gained from the optimal regimen can decrease in comparison to reasonable regimens. This has the effect of complicating the calculation of optimal regimens in a clinical setting, and may explain why results in experimental oncology fail to carry over to clinical oncology.