Using vitality indicators to predict survival of aquatic animals released from fisheries.

Estimating the survival probability of animals released from fisheries can improve the overall understanding of animal biology with implications for fisheries management, conservation and animal welfare. Vitality indicators are simple visual measures of animal condition that change in response to stressors (like fisheries capture) and can be assessed to predict post-release survival. These indicators typically include immediate reflex responses which are typically combined into a score. Vitality indicators are straight-forward and non-invasive metrics that allow users to quantify how close (or far) an animal is from a normal, 'healthy' or baseline state, which in turn can be correlated with outcomes such as survival probability, given appropriate calibration. The literature on using vitality indicators to predict post-release survival of animals has grown rapidly over the past decade. We identified 136 papers that used vitality indicators in a fisheries context. These studies were primarily focused on marine and freshwater fishes, with a few examples using herptiles and crustaceans. The types of vitality indicators are diverse and sometimes taxa-specific (e.g. pinching leg of turtles, spraying water at nictitating membrane of sharks) with the most commonly used indicators being those that assess escape response or righting response given the vulnerability of animals when those reflexes are impaired. By presenting Pacific salmon fisheries as a case study, we propose a framework for using vitality indicators to predict survival across taxa and fisheries.

Evaluating the influence of marine protected areas on surf zone fish.

Marine protected areas (MPAs) globally serve conservation and fisheries management goals, generating positive effects in some marine ecosystems. Surf zones and sandy beaches, critical ecotones bridging land and sea, play a pivotal role in the life cycles of numerous fish species and serve as prime areas for subsistence and recreational fishing. Despite their significance, these areas remain understudied when evaluating the effects of MPAs. We compared surf zone fish assemblages inside and outside MPAs across 3 bioregions in California (USA). Using seines and baited remote underwater videos (BRUVs), we found differences in surf zone fish inside and outside MPAs in one region. Inside south region MPAs, we observed higher abundance (Tukey's honest significant difference [HSD] = 0.83, p = 0.0001) and richness (HSD = 0.22, p = 0.0001) in BRUVs and greater biomass (HSD = 0.32, p = 0.0002) in seine surveys compared with reference sites. Selected live-bearing, fished taxa were positively affected by MPAs. Elasmobranchs displayed greater abundance in BRUV surveys and higher biomass in seine surveys inside south region MPAs (HSD = 0.35, p = 0.0003 and HSD = 0.23, p = 0.008, respectively). Although we observed no overall MPA signal for Embiotocidae, abundances of juvenile and large adult barred surfperch (Amphistichus argenteus), the most abundant fished species, were higher inside MPAs (K-S test D = 0.19, p < 0.0001). Influence of habitat characteristics on MPA performance indicated surf zone width was positively associated with fish abundance and biomass but negatively associated with richness. The south region had the largest positive effect size on all MPA performance metrics. Our findings underscored the variability in species richness and composition across regions and survey methods that significantly affected differences observed inside and outside MPAs. A comprehensive assessment of MPA performance should consider specific taxa, their distribution, and the effects of habitat factors and geography.

Evaluación de la influencia de las áreas marinas protegidas sobre los peces de la zona de rompientes Resumen Las áreas marinas protegidas (AMP) cumplen los objetivos de conservación y manejo de pesquerías a nivel mundial, lo que genera efectos positivos en algunos ecosistemas marinos. Las zonas de rompientes y las playas arenosas, ecotonos importantes que conectan la tierra con el mar, tienen un papel esencial en el ciclo de vida de varios peces y fungen como áreas óptimas para la pesca recreativa y de sustento. A pesar de su importancia, estas áreas están poco estudiadas con respecto a la evaluación del efecto de las AMP. Comparamos la composición de peces del área de rompientes dentro y fuera de las AMP de tres bioregiones de California, EUA. Usamos chinchorros y videos submarinos con carnada (BRUVs) y descubrimos diferencias en los peces de la zona de rompientes dentro y fuera de las AMP en una región. Dentro de las AMP de la región sur observamos una mayor abundancia (diferencia significativa honesta de Tukey [DSH]  =  0.83, p = 0.0001) y riqueza (DSH  =  0.22, p = 0.0001) en los BRUV y una mayor biomasa (DSH  =  0.32, p = 0.0002) en los censos con chinchorro en comparación con los sitios de referencia. Los taxones seleccionados de peces de sustento fueron afectados de manera positiva por las AMP. Los elasmobranquios mostraron una mayor abundancia en los BRUV y una mayor biomasa en los censos con chinchorro dentro de las AMP de la región sur (DSH  =  0.35, p = 0.0003 y DSH  =  0.23, p = 0.008, respectivamente). Aunque no observamos una señal generalizada de las AMP para la familia Embiotocidae, la abundancia de Amphistichus argenteus juveniles y adultos, la especie pescada más abundante, fue mayor dentro de las AMP (prueba K­S D  =  0.19, p < 0.0001). La influencia de las características del hábitat sobre el desempeño de las AMP indicó que el ancho de la zona de rompientes está asociado de forma positiva con la abundancia y biomasa de los peces, pero de forma negativa con la riqueza. La región sur tuvo el mayor tamaño de efecto positivo sobre todas las medidas de desempeño de las AMP. Nuestros hallazgos destacan la variabilidad en la riqueza y composición de especies en todas las regiones y los censos que afectan significativamente las diferencias observadas dentro y fuera de las AMP. Una evaluación completa del desempeño de las AMP debe considerar taxones específicos, su distribución y el efecto de los factores de hábitat y la geografía.

Factors Affecting Age of Initial Specialty Clinic Evaluation Among Infants with Sickle Cell Disease in Kingston, Jamaica.

OBJECTIVES: To evaluate the effectiveness of newborn screening for sickle cell disease in eastern Jamaica by determining what proportion of screen-positive infants were registered with the Sickle Cell Unit by 2 months (60 days) of age and identifying parents' perceptions of facilitators and barriers impacting age at registration. STUDY DESIGN: This cross-sectional study used a mixed method approach. Ages at diagnosis confirmation and first clinic visit were recorded for screen-positive infants born between February 1, 2015, and November 15, 2017. All parents were invited to complete the survey, and early and late attendees were invited to participate in the qualitative aspect of the study. A researcher-designed questionnaire and an interview guide based on the Capability, Opportunity, Motivation, Behavior, and health belief models examined factors that may affect time to registration. Quantitative data were analyzed to yield descriptive statistics using Stata®v14. All interview data were coded. Similar codes were grouped together into themes. RESULTS: Most (97.7%) of the 133 screen-positive infants had their diagnosis confirmed. Only 40% had their first clinic visit by age 60 days. Denial of the diagnosis, poor communication, and the costs of treatment and transportation were perceived barriers to registration, whereas family support was a facilitator. CONCLUSIONS: Diagnosis confirmation was almost universal, but most infants did not attend clinic by 2 months of age. In-depth interviews have identified several facilitators and barriers that can be targeted to improve early registration.

COSMOS next generation - A public knowledge base leveraging chemical and biological data to support the regulatory assessment of chemicals.

The COSMOS Database (DB) was originally established to provide reliable data for cosmetics-related chemicals within the COSMOS Project funded as part of the SEURAT-1 Research Initiative. The database has subsequently been maintained and developed further into COSMOS Next Generation (NG), a combination of database and in silico tools, essential components of a knowledge base. COSMOS DB provided a cosmetics inventory as well as other regulatory inventories, accompanied by assessment results and in vitro and in vivo toxicity data. In addition to data content curation, much effort was dedicated to data governance - data authorisation, characterisation of quality, documentation of meta information, and control of data use. Through this effort, COSMOS DB was able to merge and fuse data of various types from different sources. Building on the previous effort, the COSMOS Minimum Inclusion (MINIS) criteria for a toxicity database were further expanded to quantify the reliability of studies. COSMOS NG features multiple fingerprints for analysing structure similarity, and new tools to calculate molecular properties and screen chemicals with endpoint-related public profilers, such as DNA and protein binders, liver alerts and genotoxic alerts. The publicly available COSMOS NG enables users to compile information and execute analyses such as category formation and read-across. This paper provides a step-by-step guided workflow for a simple read-across case, starting from a target structure and culminating in an estimation of a NOAEL confidence interval. Given its strong technical foundation, inclusion of quality-reviewed data, and provision of tools designed to facilitate communication between users, COSMOS NG is a first step towards building a toxicological knowledge hub leveraging many public data systems for chemical safety evaluation. We continue to monitor the feedback from the user community at support@mn-am.com.

Ready student one: Exploring the predictors of student learning in virtual reality.

Immersive virtual reality (VR) has enormous potential for education, but classroom resources are limited. Thus, it is important to identify whether and when VR provides sufficient advantages over other modes of learning to justify its deployment. In a between-subjects experiment, we compared three methods of teaching Moon phases (a hands-on activity, VR, and a desktop simulation) and measured student improvement on existing learning and attitudinal measures. While a substantial majority of students preferred the VR experience, we found no significant differences in learning between conditions. However, we found differences between conditions based on gender, which was highly correlated with experience with video games. These differences may indicate certain groups have an advantage in the VR setting.

RNase L Antiviral Activity Is Not a Critical Component of the Oas1b-Mediated Flavivirus Resistance Phenotype.

In mice, resistance to central nervous system (CNS) disease induced by members of the genus Flavivirus is conferred by an allele of the 2'-5' oligoadenylate synthetase 1b gene that encodes the inactive full-length protein (Oas1b-FL). The susceptibility allele encodes a C-terminally truncated protein (Oas1b-tr). We show that the efficiency of neuron infection in the brains of resistant and susceptible mice is similar after an intracranial inoculation of two flaviviruses, but amplification of viral proteins and double-stranded RNA (dsRNA) is inhibited in infected neurons in resistant mouse brains at later times. Active OAS proteins detect cytoplasmic dsRNA and synthesize short 2'-5'-linked oligoadenylates (2'-5'A) that interact with the latent endonuclease RNase L, causing it to dimerize and cleave single-stranded RNAs. To evaluate the contribution of RNase L to the resistance phenotype in vivo, we created a line of resistant RNase L-/- mice. Evidence of RNase L activation in infected RNase L+/+ mice was indicated by higher levels of viral RNA in the brains of infected RNase L-/- mice. Activation of type I interferon (IFN) signaling was detected in both resistant and susceptible brains, but Oas1a and Oas1b mRNA levels were lower in RNase L+/+ mice of both types, suggesting that activated RNase L also has a proflaviviral effect. Inhibition of virus replication was robust in resistant RNase L-/- mice, indicating that activated RNase L is not a critical factor in mediating this phenotype.IMPORTANCE The mouse genome encodes a family of Oas proteins that synthesize 2'-5'A in response to dsRNA. 2'-5'A activates the endonuclease RNase L to cleave single-stranded viral and cellular RNAs. The inactive, full-length Oas1b protein confers flavivirus-specific disease resistance. Although similar numbers of neurons were infected in resistant and susceptible brains after an intracranial virus infection, viral components amplified only in susceptible brains at later times. A line of resistant RNase L-/- mice was used to evaluate the contribution of RNase L to the resistance phenotype in vivo Activation of RNase L antiviral activity by flavivirus infection was indicated by increased viral RNA levels in the brains of RNase L-/- mice. Oas1a and Oas1b mRNA levels were higher in infected RNase L-/- mice, indicating that activated RNase L also have a proflaviviral affect. However, the resistance phenotype was equally robust in RNase L-/- and RNase L+/+ mice.

Next generation physiologically based kinetic (NG-PBK) models in support of regulatory decision making.

The fields of toxicology and chemical risk assessment seek to reduce, and eventually replace, the use of animals for the prediction of toxicity in humans. In this context, physiologically based kinetic (PBK) modelling based on in vitro and in silico kinetic data has the potential to a play significant role in reducing animal testing, by providing a methodology capable of incorporating in vitro human data to facilitate the development of in vitro to in vivo extrapolation of hazard information. In the present article, we discuss the challenges in: 1) applying PBK modelling to support regulatory decision making under the toxicology and risk-assessment paradigm shift towards animal replacement; 2) constructing PBK models without in vivo animal kinetic data, while relying solely on in vitro or in silico methods for model parameterization; and 3) assessing the validity and credibility of PBK models built largely using non-animal data. The strengths, uncertainties, and limitations of PBK models developed using in vitro or in silico data are discussed in an effort to establish a higher degree of confidence in the application of such models in a regulatory context. The article summarises the outcome of an expert workshop hosted by the European Commission Joint Research Centre (EC-JRC) - European Union Reference Laboratory for Alternatives to Animal Testing (EURL ECVAM), on "Physiologically-Based Kinetic modelling in risk assessment - reaching a whole new level in regulatory decision-making" held in Ispra, Italy, in November 2016, along with results from an international survey conducted in 2017 and recently reported activities occurring within the PBK modelling field. The discussions presented herein highlight the potential applications of next generation (NG)-PBK modelling, based on new data streams.

Gender influences on the health of adolescents with sickle cell disease.

The current study examines gender effects on disease knowledge and quality of life in adolescents with sickle cell disease (SCD) in Jamaica. We report the baseline results on 76 girls and 74 boys with mean age (16.9 ± 1.8 vs. 16.2 ±2.0 years), recruited in a larger intervention study. Girls had higher knowledge scores (15.3 ± 4.2 vs. 13.3 ± 4.2 p=.004), poorer overall QOL scores (70.1 ± 19.6 vs. 77.2 ± 17.8 p=0.02) but similar severity scores to boys. Girls also had significantly lower scores on many QOL domain scores: Pain occurrences over the course the past month (Pain and Hurt:77.49 ± 23.3 vs. 85.37 ± 17.13); concerns about seeking health services for pain (Worry1:63.73 ± 26.21 vs. 75.33 ± 24.62); confidence in self-management & treatment effects (Treatment: 72.25 ± 23.6 vs. 80.73 ± 18.90) and SCD disclosure & empathy from others (Communication II: 47.44 ± 1.02 vs. 61.71 ± 29.41). Knowledge was positively predicted by age, higher education, greater household possessions and was higher in girls; whereas QOL was lower in girls and those with greater disease severity and higher with higher education. In conclusion, there is a significant gender differential in disease knowledge and QOL among adolescents with SCD. Interventions will need to address the lower QOL in girls and lower disease knowledge among boys.

Molecular fingerprint-derived similarity measures for toxicological read-across: Recommendations for optimal use.

Computational approaches are increasingly used to predict toxicity due, in part, to pressures to find alternatives to animal testing. Read-across is the "new paradigm" which aims to predict toxicity by identifying similar, data rich, source compounds. This assumes that similar molecules tend to exhibit similar activities i.e. molecular similarity is integral to read-across. Various of molecular fingerprints and similarity measures may be used to calculate molecular similarity. This study investigated the value and concordance of the Tanimoto similarity values calculated using six widely used fingerprints within six toxicological datasets. There was considerable variability in the similarity values calculated from the various molecular fingerprints for diverse compounds, although they were reasonably concordant for homologous series acting via a common mechanism. The results suggest generic fingerprint-derived similarities are likely to be optimally predictive for local datasets, i.e. following sub-categorisation. Thus, for read-across, generic fingerprint-derived similarities are likely to be most predictive after chemicals are placed into categories (or groups), then similarity is calculated within those categories, rather than for a whole chemically diverse dataset.

Trends in vitamin D supplement use in a general female and breast cancer population in Ireland: A repeated cross-sectional study.

BACKGROUND: Vitamin D has been linked with improved survival after breast cancer diagnosis but little is known about prescribing rates. This study investigates trends in vitamin D supplement use in both a general female and breast cancer population. METHODS: Women with a breast cancer diagnosis were identified from the National Cancer Registry of Ireland (n = 19870). Women who had any vitamin D claim between 2005 and 2011 were identified from pharmacy claims data (n = 8556). Prevalence rates were calculated as a proportion of all eligible women and by age (< 55 years, ≥ 55 years). Poisson regression was used to compare rates of vitamin D prescribing across years (risk ratio (RR), 95% CI). RESULTS: There was a statistically significant increase in women with a claim for vitamin D between 2005-2011, with the largest increase among breast cancer patients aged ≥ 55 years (RR = 2.26; 95% CI, 2.11-2.42). CONCLUSION: This may have significant public health implications if associations between vitamin D and improved breast cancer survival prove to be causal.

A Catalog of Spectra, Albedos, and Colors of Solar System Bodies for Exoplanet Comparison.

We present a catalog of spectra and geometric albedos, representative of the different types of solar system bodies, from 0.45 to 2.5 µm. We analyzed published calibrated, uncalibrated spectra, and albedos for solar system objects and derived a set of reference spectra and reference albedos for 19 objects that are representative of the diversity of bodies in our solar system. We also identified previously published data that appear contaminated. Our catalog provides a baseline for comparison of exoplanet observations to 19 bodies in our own solar system, which can assist in the prioritization of exoplanets for time intensive follow-up with next-generation extremely large telescopes and space-based direct observation missions. Using high- and low-resolution spectra of these solar system objects, we also derive colors for these bodies and explore how a color-color diagram could be used to initially distinguish between rocky, icy, and gaseous exoplanets. We explore how the colors of solar system analog bodies would change when orbiting different host stars. This catalog of solar system reference spectra and albedos is available for download through the Carl Sagan Institute.

De novo vitamin D supplement use post-diagnosis is associated with breast cancer survival.

PURPOSE: Experimental laboratory data have indicated a protective effect of vitamin D on breast cancer progression, while epidemiological evidence is growing. Using pharmacy claims data, this study investigates the association between vitamin D supplement use initiated after a breast cancer diagnosis and associated mortality. METHODS: Women aged 50-80 years with a record of invasive breast cancer were identified on the National Cancer Registry Ireland database (n = 5417). Initiation of de novo vitamin D post-diagnosis was identified from linked national prescription data (n = 2581, 49%). Multivariate Cox proportional hazards models were used to estimate adjusted HRs (95% CIs) for breast cancer-specific mortality. RESULTS: There was a 20% reduction in breast cancer-specific mortality in de novo vitamin D users (modelled as a time-varying variable) compared to non-users (HR 0.80; 95% CI 0.64-0.99, p = 0.048) and the reduction was greater at 49% (HR 0.51; 95% CI 0.34-0.74, p < 0.001), if vitamin D was initiated soon after the breast cancer diagnosis (within 6 months). CONCLUSIONS: In this large national breast cancer cohort, de novo vitamin D use post-diagnosis was found to be associated with a reduction in breast cancer-specific mortality. Vitamin D, therefore, has the potential as a non-toxic and inexpensive agent to improve survival in breast cancer patients. Findings support the need for RCTs exploring the effect of vitamin D supplementation on breast cancer survival.

In vivo assembly of a truncated H subunit mutant of the Rhodobacter sphaeroides photosynthetic reaction centre and direct electron transfer from the QA quinone to an electrode.

We address a challenge in the engineering of proteins to redirect electron transfer pathways, using the bacterial photosynthetic reaction centre (RC) pigment-protein complex. Direct electron transfer is shown to occur from the QA quinone of the Rhodobacter sphaeroides RC containing a truncated H protein and bound on the quinone side to a gold electrode. In previous reports of binding to the quinone side of the RC, electron transfer has relied on the use of a soluble mediator between the RC and an electrode, in part because the probability of QB quinone reduction is much greater than that of direct electron transfer through the large cytoplasmic domain of the H subunit, presenting a ~ 25 Å barrier. A series of C-terminal truncations of the H subunit were created to expose the quinone region of the RC L and M proteins, and all truncated RC H mutants assembled in vivo. The 45M mutant was designed to contain only the N-terminal 45 amino acid residues of the H subunit including the membrane-spanning α-helix; the mutant RC was stable when purified using the detergent N-dodecyl-ß-D-maltoside, contained a near-native ratio of bacteriochlorophylls to bacteriopheophytins, and showed a charge-separated state of [Formula: see text]. The 45M-M229 mutant RC had a Cys residue introduced in the vicinity of the QA quinone on the newly exposed protein surface for electrode attachment, decreasing the distance between the quinone and electrode to ~ 12 Å. Steady-state photocurrents of up to around 200 nA/cm2 were generated in the presence of 20 mM hydroquinone as the electron donor to the RC. This novel configuration yielded photocurrents orders of magnitude greater than previous reports of electron transfer from the quinone region of RCs bound in this orientation to an electrode.

Improving disease knowledge in 6- to 10-year-olds with sickle cell disease: A quasi-experimental study.

BACKGROUND: Increasing knowledge and understanding of disease is known to improve outcomes in persons living with a chronic illness. In this paper, we aim to compare the disease knowledge of children with sickle cell disease (SCD), age 6-10 years, who received an intervention (an educational colouring book on SCD) geared towards improving disease knowledge, to those who did not received the colouring book. METHODS: A quasi-experimental study was conducted where disease knowledge was determined in 56 children who had received the colouring book and compared to 60 children who did not receive this intervention. RESULTS: The mean knowledge score was significantly higher in the intervention group (mean difference = 2.65; 95% CI [1.43, 3.86]), as well as in older children and in those in higher grades but there was no difference between sexes. In a multiple regression model (adjusted R2 : 0.39; p value < .001), knowledge score was significantly higher in those who received the intervention (ß: 2.62; 95% CI [1.48, 3.76]) while adjusting for age, gender, persons living at home, and the father's employment status. CONCLUSION: The study highlights that a simple, inexpensive (cost: US$1/book) child-friendly intervention can significantly improve knowledge about SCD even in young children. It also underlines various social factors that are associated with children's understanding of their disease.

Morning surge in blood pressure using a random-effects multiple-component cosinor model.

Blood pressure (BP) fluctuates throughout the day. The pattern it follows represents one of the most important circadian rhythms in the human body. For example, morning BP surge has been suggested as a potential risk factor for cardiovascular events occurring in the morning, but the accurate quantification of this phenomenon remains a challenge. Here, we outline a novel method to quantify morning surge. We demonstrate how the most commonly used method to model 24-hour BP, the single cosinor approach, can be extended to a multiple-component cosinor random-effects model. We outline how this model can be used to obtain a measure of morning BP surge by obtaining derivatives of the model fit. The model is compared with a functional principal component analysis that determines the main components of variability in the data. Data from the Mitchelstown Study, a population-based study of Irish adults (n = 2047), were used where a subsample (1207) underwent 24-hour ambulatory blood pressure monitoring. We demonstrate that our 2-component model provided a significant improvement in fit compared with a single model and a similar fit to a more complex model captured by b-splines using functional principal component analysis. The estimate of the average maximum slope was 2.857 mmHg/30 min (bootstrap estimates; 95% CI: 2.855-2.858 mmHg/30 min). Simulation results allowed us to quantify the between-individual SD in maximum slopes, which was 1.02 mmHg/30 min. By obtaining derivatives we have demonstrated a novel approach to quantify morning BP surge and its variation between individuals. This is the first demonstration of cosinor approach to obtain a measure of morning surge.

Characterisation of data resources for in silico modelling: benchmark datasets for ADME properties.

INTRODUCTION: The cost of in vivo and in vitro screening of ADME properties of compounds has motivated efforts to develop a range of in silico models. At the heart of the development of any computational model are the data; high quality data are essential for developing robust and accurate models. The characteristics of a dataset, such as its availability, size, format and type of chemical identifiers used, influence the modelability of the data. Areas covered: This review explores the usefulness of publicly available ADME datasets for researchers to use in the development of predictive models. More than 140 ADME datasets were collated from publicly available resources and the modelability of 31 selected datasets were assessed using specific criteria derived in this study. Expert opinion: Publicly available datasets differ significantly in information content and presentation. From a modelling perspective, datasets should be of adequate size, available in a user-friendly format with all chemical structures associated with one or more chemical identifiers suitable for automated processing (e.g. CAS number, SMILES string or InChIKey). Recommendations for assessing dataset suitability for modelling and publishing data in an appropriate format are discussed.

Accuracy and cost-effectiveness of dynamic contrast-enhanced CT in the characterisation of solitary pulmonary nodules-the SPUtNIk study.

INTRODUCTION: Solitary pulmonary nodules (SPNs) are common on CT. The most cost-effective investigation algorithm is still to be determined. Dynamic contrast-enhanced CT (DCE-CT) is an established diagnostic test not widely available in the UK currently. METHODS AND ANALYSIS: The SPUtNIk study will assess the diagnostic accuracy, clinical utility and cost-effectiveness of DCE-CT, alongside the current CT and 18-flurodeoxyglucose-positron emission tomography) (18FDG-PET)-CT nodule characterisation strategies in the National Health Service (NHS). Image acquisition and data analysis for 18FDG-PET-CT and DCE-CT will follow a standardised protocol with central review of 10% to ensure quality assurance. Decision analytic modelling will assess the likely costs and health outcomes resulting from incorporation of DCE-CT into management strategies for patients with SPNs. ETHICS AND DISSEMINATION: Approval has been granted by the South West Research Ethics Committee. Ethics reference number 12/SW/0206. The results of the trial will be presented at national and international meetings and published in an Health Technology Assessment (HTA) Monograph and in peer-reviewed journals. TRIAL REGISTRATION NUMBER: ISRCTN30784948; Pre-results.

Data from subjects receiving intrathecal laronidase for cervical spinal stenosis due to mucopolysaccharidosis type I.

Five subjects with mucopolysaccharidosis type I and symptomatic cervical spinal stenosis received intrathecal laronidase in a 4-month pilot study and/or a 12-month extension study [1]. Clinical descriptions of study subjects, nonserious adverse events, individual data tables, and scoring system methods are provided. There were ten nonserious adverse events that occurred in more than one study subject. Somatosensory evoked potentials were absent in two subjects and normal in two subjects, limiting their utility as an endpoint. There were no significant changes in magnetic resonance imaging of cervical spinal cord or brain, pulmonary function tests, or cerebrospinal fluid opening pressure. These data are presented along with the scoring methods used in evaluation of the study subjects.

Functional heterogeneity of calretinin-expressing neurons in the mouse superficial dorsal horn: implications for spinal pain processing.

KEY POINTS: The superficial spinal dorsal horn contains a heterogeneous population of neurons that process sensory inputs. Information on the properties of excitatory interneurons in this region is limited. As calretinin is a protein thought to be restricted to an excitatory population in this region, the aim of this study was to characterize calretinin-expressing neurons. Most calretinin cells (85%) exhibited large A-type potassium currents and delayed firing action potential discharge, and received strong excitatory synaptic input, whereas the remainder exhibited hyperpolarization-activated cation currents and low threshold T-type calcium currents, and tonic- or initial bursting firing patterns, and received weak excitatory synaptic input. These respective features are consistent with properties of excitatory and inhibitory interneuron populations in this region of the spinal cord. Our findings have resolved a previously unidentified population of inhibitory interneurons. Furthermore, the contrasting excitability patterns of excitatory and inhibitory calretinin-expressing neurons suggest that they play distinct roles in spinal sensory processing circuits. ABSTRACT: Neurons in the superficial dorsal horn (SDH) of the spinal cord play an important role in nociceptive, thermal, itch and light touch sensations. Excitatory interneurons comprise ∼65% of all SDH neurons but surprisingly few studies have investigated their role in spinal sensory processing. Here we use a transgenic mouse to study putative excitatory SDH neurons that express the calcium binding protein calretinin (CR). Our immunocytochemical, morphological and electrophysiological analysis identified two distinct populations of CR-expressing neurons, which we termed 'Typical' and 'Atypical'. Typical CR-expressing neurons comprised ∼85% of the population and exhibited characteristic excitatory interneuron properties including delayed firing discharge, large rapid A-type potassium currents, and central, radial or vertical cell morphologies. Atypical neurons exhibited properties consistent with inhibitory interneurons, including tonic firing or initial bursting discharge, Ih currents, and islet cell morphology. Although both Typical and Atypical CR-expressing neurons responded to noxious peripheral stimulation, the excitatory drive onto Typical CR-expressing neurons was much stronger. Furthermore, Atypical CR-expressing cells comprise at least two functionally distinct subpopulations based on their responsiveness to noxious peripheral stimulation and neurochemical profile. Together our data suggest CR expression is not restricted to excitatory neurons in the SDH. Under normal conditions, the contribution of 'Typical' excitatory CR-expressing neurons to overall SDH excitability may be limited by the presence of A-type potassium currents, which limit the effectiveness of their strong excitatory input. Their contribution may, however, be increased in pathological situations where A-type potassium currents are decreased. By contrast, 'Atypical' inhibitory neurons with their excitable phenotype but weak excitatory input may be more easily recruited during increased peripheral stimulation.