Effectiveness of wheelchair skills training for improving manual wheelchair mobility in children and adolescents: protocol for a multicenter randomized waitlist-controlled trial.

BACKGROUND: Self-directed mobility during childhood can influence development, social participation, and independent living later in life. For children who experience challenges with walking, manual wheelchairs (MWCs) provide a means for self-directed mobility. An effective MWC skills training program exists for adults, but controlled trials have not yet been documented in children and adolescents. This paper outlines the protocol for a multi-centre randomized wait-list controlled trial. The primary objective is to test the hypothesis that children and adolescents who receive MWC skills training will have higher MWC skills capacity compared to children and adolescents in the control group who receive usual care. The secondary objectives are to explore the influence of MWC skills training in children and adolescents (MWC use self-efficacy and satisfaction with participation in meaningful activities), and parents (perceived MWC skills); and to measure retention three months later. METHODS: A multi-centre, parallel-group, single-blind randomized wait-list controlled trial will be conducted. A sample of 60 children and adolescents who use MWCs will be recruited in rehabilitation centres, specialized schools, and the communities of three Canadian cities. Participants will be randomized (1:1) to the experimental (Wheelchair Skills Training Program [WSTP]) or wait-list control group (usual care). Performance-based and self-report measures will be completed at baseline (T1), three months (post-intervention, T2), and three months post-intervention (T3). The primary outcome will be MWC skills capacity post-intervention. Secondary outcomes will be MWC use self-efficacy and satisfaction with participation of the child/adolescent, and parent-perceived MWC skills. The WSTP will consist of 12 sessions, 45-60 min each, delivered 1-2 times per week by trained personnel with health professions education. Training will be customized according to the child's baseline skills and participation goals that require the use of the MWC. The wait-list control group will receive usual care for 3 months and then receive the WSTP after completing T2 evaluations. Data will be analysed using ANCOVA (controlling for baseline scores). DISCUSSION: MWC skills training may be one way to improve self-directed mobility and related outcomes for children and adolescents. The results of this multi-centre randomized wait-list controlled trial will allow for the effectiveness of the intervention to be evaluated in a variety of clinical contexts and geographical regions. TRIAL REGISTRATION: ClinicalTrials.gov: NCT05564247, Version October 3, 2022.

The independent and interactive associations of physical activity intensity and vitamin D status with bone mineral density in prepubertal children: the PANIC Study.

It is unclear how physical activity intensity and vitamin D status are related to bone health in prepubertal children. We found positive associations between vitamin D status and moderate-to-vigorous physical activity with bone in boys and girls. This highlights the importance of lifestyle factors for skeletal health prepuberty. INTRODUCTION: The sex-specific independent and interactive associations of physical activity (PA) intensity and serum 25-hydroxyvitamin D (25(OH)D) levels with areal bone mineral density (aBMD) were investigated in prepubertal children. METHODS: The participants were 366 prepubertal Finnish children (190 boys, 176 girls) aged 6-8 years. Linear regression analysed the associations of sedentary time (ST), light PA (LPA), moderate PA (MPA), moderate-to-vigorous PA (MVPA) and vigorous PA (VPA) measured by accelerometery, and serum 25(OH)D with total body less head (TBLH) and lower-limb aBMD, measured by dual-energy X-ray absorptiometry. RESULTS: There was no interaction between PA intensity or serum 25(OH)D and sex with aBMD. MPA and MVPA were positively associated with TBLH and lower-limb aBMD (ß = 0.11, 95% CI 0.02-0.20, p = 0.01). Serum 25(OH)D was positively associated with TBLH and lower-limb aBMD (ß = 0.09, 95% CI 0.01-0.18, p = 0.03). There were no interactions between PA intensity and serum 25(OH)D with aBMD. CONCLUSION: Vitamin D status, MPA and MVPA levels in active prepubertal children were positively associated with aBMD. The influence of MVPA is due to the MPA component, though our findings regarding the role of VPA should be interpreted with caution, as shorter accelerometer epochs are needed to more accurately assess VPA. This study adds evidence to the promotion of MPA and behaviours to encourage optimal vitamin D status in supporting skeletal health in childhood, though these need not be used in conjunction to be beneficial, and a sex-specific approach is not necessary in prepubertal children. TRIAL REGISTRATION NUMBER: NCT01803776 . Date of registration: 4/03/2013.

A CTSA One Health Alliance guidance on institutional review of veterinary clinical studies.

Harmonized institutional processes and reviewer training are vital to maintain integrity and ethical rigor of the veterinary clinical research pipeline and are a prerequisite to future work that might establish centralized or single-site ethical and regulatory review to ease initiation of multi-center studies. Funded by a CTSA One Health Alliance (COHA) pilot award, a diverse working group of veterinary clinicians and institutional representatives was convened in February 2020 to develop a guidance document detailing broadly agreed upon practices for ethical review and approval of veterinary clinical studies conducted in the United States.The working group defined key areas of need for consensus, developed a set of associated guidelines, and circulated these for review by COHA's fifteen member institutions. Six focus areas were identified by the working group and included vital items of protocol review, composition of the review committee, post-approval monitoring and adverse event reporting, consideration of special circumstances such as satellite sites and the use of healthy veterinary subjects in research, and the informed consent process.This document outlines a broadly agreed-upon framework through which to approach vital items associated with veterinary clinical study protocol review and approval. These approaches represent current best practice in the review and approval of veterinary clinical studies, and can serve as a guidance for veterinary clinician-scientists and regulatory experts, to ensure robust and ethically conducted studies that can contribute to the advancement of both animal and human health.

Emergency Department Versus Operating Suite Intubation in Operative Trauma Patients: Does Location Matter?

BACKGROUND: Decreasing the time from patient arrival to definitive surgical care in injured patients requiring an operation improves outcomes. We sought to study the effect of intubation location (emergency department versus operating suite) on time to definitive surgical care. We hypothesized that patients requiring emergency surgical interventions intubated in the emergency department would have shorter times to definitive care when compared to patients intubated in the operating suite. METHODS: All injured patients with a preoperative emergency department dwell time of less than 30 min and undergoing emergency operative procedures with the trauma surgery service at an urban Level I center (2010-2017) were analyzed. Demographics, clinical variables, and outcomes were assessed in relation to emergency department intubation versus operating suite intubation. The primary study endpoint was time to initiation of definitive surgical care, defined as the total elapsed time from emergency department arrival until operating room incision time. To investigate the relationship between clinical variables and time, multivariable regression was performed. RESULTS: In total, 241 patients were included. In total, 138 patients were intubated in the emergency department and 103 patients were intubated in the operative suite. There was no difference between patients intubated in the emergency department and those intubated in the operating room with respect to age, gender, injury mechanism, initial heart rate or systolic blood pressure. Emergency department patients were more likely to sustain post-intubation, traumatic cardiopulmonary arrest (8.0 vs. 0.9%; p = 0.014). No statistical difference in total elapsed time from arrival to definitive surgical care was appreciated between study groups (41 vs. 43 min; p = 0.064). After controlling for clinical variables, emergency department intubation was not associated with time to definitive care (p = 0.386) in the multiple variable regression analysis. CONCLUSION: When emergency department and operative suite intubation patients were compared, emergency department intubation did not decrease total elapsed time until definitive surgery but was associated with post-intubation, traumatic cardiopulmonary arrest.

MSTO1 mutations cause mtDNA depletion, manifesting as muscular dystrophy with cerebellar involvement.

MSTO1 encodes a cytosolic mitochondrial fusion protein, misato homolog 1 or MSTO1. While the full genotype-phenotype spectrum remains to be explored, pathogenic variants in MSTO1 have recently been reported in a small number of patients presenting with a phenotype of cerebellar ataxia, congenital muscle involvement with histologic findings ranging from myopathic to dystrophic and pigmentary retinopathy. The proposed underlying pathogenic mechanism of MSTO1-related disease is suggestive of impaired mitochondrial fusion secondary to a loss of function of MSTO1. Disorders of mitochondrial fusion and fission have been shown to also lead to mitochondrial DNA (mtDNA) depletion, linking them to the mtDNA depletion syndromes, a clinically and genetically diverse class of mitochondrial diseases characterized by a reduction of cellular mtDNA content. However, the consequences of pathogenic variants in MSTO1 on mtDNA maintenance remain poorly understood. We present extensive phenotypic and genetic data from 12 independent families, including 15 new patients harbouring a broad array of bi-allelic MSTO1 pathogenic variants, and we provide functional characterization from seven MSTO1-related disease patient fibroblasts. Bi-allelic loss-of-function variants in MSTO1 manifest clinically with a remarkably consistent phenotype of childhood-onset muscular dystrophy, corticospinal tract dysfunction and early-onset non-progressive cerebellar atrophy. MSTO1 protein was not detectable in the cultured fibroblasts of all seven patients evaluated, suggesting that pathogenic variants result in a loss of protein expression and/or affect protein stability. Consistent with impaired mitochondrial fusion, mitochondrial networks in fibroblasts were found to be fragmented. Furthermore, all fibroblasts were found to have depletion of mtDNA ranging from 30 to 70% along with alterations to mtDNA nucleoids. Our data corroborate the role of MSTO1 as a mitochondrial fusion protein and highlight a previously unrecognized link to mtDNA regulation. As impaired mitochondrial fusion is a recognized cause of mtDNA depletion syndromes, this novel link to mtDNA depletion in patient fibroblasts suggests that MSTO1-deficiency should also be considered a mtDNA depletion syndrome. Thus, we provide mechanistic insight into the disease pathogenesis associated with MSTO1 mutations and further define the clinical spectrum and the natural history of MSTO1-related disease.

The Spinal Ependymal Layer in Health and Disease.

Ependymal cells are epithelial support cells that line the central canal and ventricular cavities of the central nervous system, providing the interface between the cerebrospinal fluid and the parenchyma of the brain and spinal cord. The spinal ependymal layer (SEL) is composed of 3 main cell types: tanycytes, ependymocytes, and cerebrospinal fluid-contacting neurons. A fourth cell type, termed the supraependymal cell, is also occasionally described. Cells of the SEL show restricted proliferative capacity in health but display neural stem cell properties both in vitro and in vivo in various disease states. A growing body of literature is devoted to the regenerative roles of the SEL, particularly in the context of spinal cord injury, where mechanical damage to the spinal cord leads to a significant increase in SEL proliferation. SEL-derived cell progeny migrate to sites of injury within the injured spinal cord parenchyma and contribute primarily to glial scar formation. In additional to their role as endogenous neural stem cells, cells of the SEL may be an important source of cytokines and other cell signaling molecules, such as tumor necrosis factor, heat shock proteins, and various growth factors. The SEL has become of recent interest to neuroscience researchers because of its potential to participate in and respond to diseases affecting the spinal cord (eg, traumatic spinal cord injury) and neurodegenerative disease. The intimate association of the SEL with the cerebrospinal fluid makes intrathecal therapies a viable option, and recent studies highlight the potential promise of treatments that augment SEL responses to disease.

Spinal Cord Ependymal Responses to Naturally Occurring Traumatic Spinal Cord Injury in Dogs.

The spinal cord ependymal layer (SEL) is a recent focus in spinal cord injury (SCI) research because of its potential to serve as a source of endogenous neural stem cells. Dogs are an important spontaneous model of SCI; however, there is a paucity of information available in the literature regarding the canine SEL. Here we describe the histologic appearance and immunohistochemical staining patterns of the SEL in normal dogs (n = 4) and dogs with acute SCI caused by intervertebral disk extrusion (n = 7). Immunohistochemical staining for PCNA, Ki-67, caspase 3, E-cadherin, GFAP, and vimentin was employed in both groups. Staining for Ki-67 was absent in the SEL of normal and SCI-affected dogs, indicating possible restricted proliferative capacity of the canine SEL acutely after SCI. GFAP-positive cells were increased after SCI at both at the lesion epicenter and at proximal spinal cord sites (P = .001 and P = .006, respectively), supporting the possibility of astrocytic differentiation within the SEL after SCI. Total E-cadherin staining did not differ between normal and SCI-affected dogs (P = .42 for lesion epicenter, P = .09 at proximal sites) and was restricted to the apical cell surface in normal dogs. After SCI, E-cadherin staining was membrane-circumferential and cytosolic in nature, indicating possible loss of cellular polarity after injury that could drive cell migration from the SEL to injury sites. Enhanced GFAP expression and changes in E-cadherin expression patterns support additional studies to evaluate the canine SEL as a source of endogenous neural precursors that may be modulated for future clinical interventions after SCI.

Patterns of circulating serotonin and related metabolites in multiparous dairy cows in the peripartum period.

Dairy cows are challenged to maintain Ca and glucose homeostasis during the transition period. Serotonin (5-HT) is a monoamine that modulates Ca and glucose homeostasis in rodents. Serotonin is positively correlated with Ca and glucose status in dairy cows on d 1 of lactation. However, the pattern of circulating concentrations of 5-HT over the course of a 305-d lactation is unknown. In this observational, longitudinal study, we examined the metabolite patterns of 5-HT, Ca, glucose, parathyroid hormone-related protein, and ß-hydroxybutyrate on 2 commercial dairy farms in south-central Wisconsin. Cows sampled on farm 1 were multiparous Jersey cows (n=30) that calved within a 23-d period; cows on farm 2 were multiparous Holstein cows (n=35) that calved within a 20-d period. Blood samples were collected daily between d -5 and d 10 relative to parturition and on d 30, 60, 90, 150, and 300 of lactation. Farms 1 and 2 were analyzed individually because of the presence of a farm effect in the initial analysis; a time effect was present on both farms. Concentrations of 5-HT decreased near parturition compared with prepartum by 57.9 and 29.5% on farm 1 and 2, respectively. Transition period 5-HT nadirs were observed on d 1 on farm 1, and on d 1 and 9 on farm 2. Serotonin recovered to prepartum concentrations by d 5 on farm 1. On farm 2, 5-HT recovered to prepartum concentrations by d 4, with a subsequent decrease of 34.6% on d 9 to a level similar to that observed on d 1. Furthermore, 5-HT increased markedly in cows on both farms near peak lactation (d 60, 90, and 150) and decreased on d 300. Compared with prepartum concentrations, Ca decreased by 34.2 and 11.2% on farms 1 and 2, respectively. Circulating total Ca nadir was observed on d 1 on both farms. Circulating 5-HT and circulating Ca were positively correlated during the early lactation period (d 1 to 5 and d 6 to 10) on farm 1 (r=0.31 and r=0.22, respectively) and d 6 to 10 on farm 2 (r=0.16). Circulating 5-HT and glucose were negatively correlated during the early lactation period (d 1 to 5) on farm 1 (r=-0.21) and during mid-lactation (d 30 to 150) on farm 2 (r=-0.26). Milk 5-HT and milk total Ca were positively correlated on farm 2 (r=0.34). These results demonstrate that 5-HT concentrations change dynamically throughout the transition period, with a pattern similar to that of total Ca concentrations. Further research using controlled experiments should be aimed at discerning the association between 5-HT and Ca and between 5-HT and glucose in dairy cows.

Short communication: Circulating serotonin (5-HT) concentrations on day 1 of lactation as a potential predictor of transition-related disorders.

The monoamine serotonin (5-hydroxytryptamine; 5-HT) has been described as a homeostatic regulator of lactation. Recently, our laboratory determined that 5-HT is involved in the regulation of calcium and glucose homeostasis during the transition period in rodents. More specifically, we demonstrate that 5-HT is responsible for calcium mobilization from bone and upregulation of hepatic gluconeogenic enzymes and mammary gland glucose transporters. Our objective was to investigate the correlation between circulating 5-HT concentrations and circulating ionized calcium, parathyroid hormone-related protein (PTHrP), and glucose concentrations on d 1 postpartum. We also investigated the correlation between circulating 5-HT and milk fever and ketosis incidence and severity in multiparous Holstein cows at the onset of lactation. Blood samples were collected from 42 multiparous cows on d 1 of lactation and analyzed for 5-HT, calcium, glucose, and PTHrP. Milk fever (determined subjectively for each cow on d 1 postpartum) and ketosis incidence and severity (scale 1 to 4, determined objectively for each cow during the first 10 d postpartum) were recorded for all animals. Serum 5-HT was positively correlated with serum calcium and with plasma PTHrP (r>0.37). Serum 5-HT was negatively correlated with milk fever incidence and with ketosis severity (most severe ketosis incidence recorded during the first 10 d postpartum; r<-0.33). Serum calcium and plasma glucose concentrations were negatively correlated with milk fever and ketosis severity, respectively (r<-0.39). These data indicate that 5-HT potentially plays a role in the regulation of calcium and glucose homeostasis during the transition period in cattle, which we previously demonstrated in rodents. Increased circulating concentrations of 5-HT might decrease milk fever at the onset of lactation and ketosis severity during the first 10 d postpartum in dairy cows. Understanding this physiological axis could help describe the underlying mechanisms associated with these periparturient metabolic disorders in dairy cows.

Using multi-frequency acoustic attenuation to monitor grain size and concentration of suspended sediment in rivers.

Multi-frequency acoustic backscatter profiles recorded with side-looking acoustic Doppler current profilers are used to monitor the concentration and size of sedimentary particles suspended in fluvial environments. Data at 300, 600, and 1200 kHz are presented from the Isère River in France where the dominant particles in suspension are silt and clay sizes. The contribution of suspended sediment to the through-water attenuation was determined for three high concentration (> 100 mg/L) events and compared to theoretical values for spherical particles having size distributions that were measured by laser diffraction in water samples. Agreement was good for the 300 kHz data, but it worsened with increasing frequency. A method for the determination of grain size using multi-frequency attenuation data is presented considering models for spherical and oblate spheroidal particles. When the resulting size estimates are used to convert sediment attenuation to concentration, the spheroidal model provides the best agreement with optical estimates of concentration, but the aspect ratio and grain size that provide the best fit differ between events. The acoustic estimates of size were one-third the values from laser grain sizing. This agreement is encouraging considering optical and acoustical instruments measure different parameters.

Habitat selection of resident and non-resident gray wolves: implications for habitat connectivity.

Habitat selection studies facilitate assessing and predicting species distributions and habitat connectivity, but habitat selection can vary temporally and among individuals, which is often ignored. We used GPS telemetry data from 96 Gray wolves (Canis lupus) in the western Great Lakes region of the USA to assess differences in habitat selection while wolves exhibited resident (territorial) or non-resident (dispersing or floating) movements and discuss implications for habitat connectivity. We used a step-selection function (SSF) to assess habitat selection by wolves exhibiting resident or non-resident movements, and modeled circuit connectivity throughout the western Great Lakes region. Wolves selected for natural land cover and against areas with high road densities, with no differences in selection among wolves when resident, dispersing, or floating. Similar habitat selection between resident and non-resident wolves may be due to similarity in environmental conditions, when non-resident movements occur largely within established wolf range rather than near the periphery or beyond the species range. Alternatively, non-resident wolves may travel through occupied territories because higher food availability or lower human disturbance outweighs risks posed by conspecifics. Finally, an absence of differences in habitat selection between resident and non-resident wolf movements may be due to other unknown reasons. We recommend considering context-dependency when evaluating differences in movements and habitat use between resident and non-resident individuals. Our results also provide independent validation of a previous species distribution model and connectivity analysis suggesting most potential wolf habitat in the western Great Lakes region is occupied, with limited connectivity to unoccupied habitat.

The pharmacokinetics of levetiracetam in healthy dogs concurrently receiving phenobarbital.

Levetiracetam (LEV) is a commonly used add-on medication in dogs with refractory epilepsy. The objective of this study was to determine if the pharmacokinetics of LEV are altered by concurrent administration of phenobarbital (PB). Six healthy dogs received a single oral dose of LEV (16.7-27.8 mg/kg). Blood samples were collected at baseline and intermittently for 24 h. The study was repeated after the dogs received oral PB (2.0-3.3 mg/kg) twice daily for 21 days. Plasma LEV levels were evaluated by high pressure liquid chromatography, and data analyzed using a compartmental model. Compared with values determined when LEV was administered alone, concurrent administration of PB resulted in a decrease in LEV peak concentration (C(max) ) from 32.39 ± 6.76 to 18.22 ± 8.97 (P = 0.0071), a decrease in elimination half-life (T(1/2) ) from 3.43 ± 0.47 to 1.73 ± 0.22 (P = 0.0005), and an increase in oral clearance from 124.93 ± 26.93 to 252.99 ± 135.43 ml/h/kg (P < 0.0001). Concurrent PB administration significantly alters the pharmacokinetics of LEV in the dog, indicating that dosage adjustments might be necessary when the drug is administered with PB.

Indications of proton-dominated cosmic-ray composition above 1.6 EeV.

We report studies of ultrahigh-energy cosmic-ray composition via analysis of depth of air shower maximum (X(max)), for air shower events collected by the High-Resolution Fly's Eye (HiRes) observatory. The HiRes data are consistent with a constant elongation rate d/d[log(E)] of 47.9+/-6.0(stat)+/-3.2(syst) g/cm2/decade for energies between 1.6 and 63 EeV, and are consistent with a predominantly protonic composition of cosmic rays when interpreted via the QGSJET01 and QGSJET-II high-energy hadronic interaction models. These measurements constrain models in which the galactic-to-extragalactic transition is the cause of the energy spectrum ankle at 4x10(18) eV.

Maturity status in male child and adolescent athletes.

AIM: Early-maturing individuals may be at an advantage in some sports. The purpose of this study was to compare maturity status between competitive male child (10-12 years old) and adolescent (14-16 years old) athletes and minimally-active, age-matched controls. METHODS: In total, 224 males were included in the study. Children (n=115) included minimally-active boys (n=34), soccer players (n=26), gymnasts (n=25) and hockey players (n=30). Adolescents (n=109) included minimally-active adolescents (n=31), soccer players (n=30), gymnasts (n=17) and hockey players (n=31). Sexual maturity was assessed using secondary sex characteristics and salivary testosterone concentration (sT). Skeletal age was also assessed, using quantitative ultrasound (Sunlight BonAgeTM). RESULTS: Within each age group, no differences were observed between sport groups in chronological age, sT or pubertal age. In children, hockey players were more skeletally mature (12.43±1.36 years) than all other groups (11.0±1.0; 11.6±1.4 and 11.7±1.4 years for soccer, gymnasts and controls, respectively). In adolescents, hockey players and gymnasts had higher skeletal maturity (16.8±1.5 and 16.9±1.6 years, respectively; P<0.05) than controls (15.99±1.13 years). CONCLUSION: While sexual and hormonal maturity does not appear to differ between similar-aged athletes of different sports, the results suggest greater skeletal maturity in hockey players, even before puberty.

Progressive muscular dystrophy in alpha-sarcoglycan-deficient mice.

Limb-girdle muscular dystrophy type 2D (LGMD 2D) is an autosomal recessive disorder caused by mutations in the alpha-sarcoglycan gene. To determine how alpha-sarcoglycan deficiency leads to muscle fiber degeneration, we generated and analyzed alpha-sarcoglycan- deficient mice. Sgca-null mice developed progressive muscular dystrophy and, in contrast to other animal models for muscular dystrophy, showed ongoing muscle necrosis with age, a hallmark of the human disease. Sgca-null mice also revealed loss of sarcolemmal integrity, elevated serum levels of muscle enzymes, increased muscle masses, and changes in the generation of absolute force. Molecular analysis of Sgca-null mice demonstrated that the absence of alpha-sarcoglycan resulted in the complete loss of the sarcoglycan complex, sarcospan, and a disruption of alpha-dystroglycan association with membranes. In contrast, no change in the expression of epsilon-sarcoglycan (alpha-sarcoglycan homologue) was observed. Recombinant alpha-sarcoglycan adenovirus injection into Sgca-deficient muscles restored the sarcoglycan complex and sarcospan to the membrane. We propose that the sarcoglycan-sarcospan complex is requisite for stable association of alpha-dystroglycan with the sarcolemma. The Sgca-deficient mice will be a valuable model for elucidating the pathogenesis of sarcoglycan deficient limb-girdle muscular dystrophies and for the development of therapeutic strategies for this disease.

The effect of malondialdehyde is modified by simian virus 40 transformation in human lung fibroblast cells.

The effects of malondialdehyde (MDA), a product of oxidative stress, on normal lung fibroblast cells (MRC5) and transformed cells (MRC5 SV2) showed differing responses between the two cell lines. MRC5 cells showed lower viability at low MDA concentrations (<250 µM) but had better viability at higher concentrations than the transformed cells. Both cell lines showed an increase in the number of micronuclei, nuclear size and a relocation of p53 to the nucleus with increasing MDA. The expression of p53 was higher in the MRC5 cells at 24 h; 2-8 fold induction vs 1-2.5 fold in the MRC5 SV2 cells, but reduced to almost zero at 48 h in the MRC5 cells. Mutation sequencing of the PCR products of a 689 bp region (residues 4640-5328) of the TP53 gene revealed MRC5 had more mutations than MRC5 SV2 cells (n = 21 and 11 respectively) and that they were predominantly insertions (MRC5 81%, MRC5 SV2 100%). A common mutation was observed in both cell lines; a G insertion at residue 4724 (n = 7) which could prove to be a mutational hotspot. These results indicate that the transformed cells are slower to respond to oxidative stress and/or mutagenic compounds. The mutation spectrum of predominantly frameshift mutations (insertions) suggests that oxidative stress plays a minimal role in smoking related lung cancer, but could be of greater importance to other lung diseases and cancer caused by exposures such as passive smokers, passive vapers and atmospheric pollutants.

Interobserver agreement of an electronic von Frey device for measuring mechanical sensory thresholds in normal dogs.

Electronic von Frey Aesthesiometry (VFA) has been previously reported as a useful method of mechanical quantitative sensory testing (QST) for evaluating neuropathic pain in dogs. Intraobserver agreement has been shown to be good to excellent; however, interobserver agreement has not been evaluated and is vital to the use of this technique in multicenter veterinary clinical trials in neuropathic pain. The goal of this study was to evaluate the interobserver agreement of sensory thresholds obtained using electronic VFA in a group of normal small breed dogs. Twenty healthy dogs (<20 kg) were recruited from the general practice population at the Ohio State University Veterinary Medical Center. Three clinically experienced yet QST novice evaluators used an electronic von Frey device to measure mechanical sensory threshold (ST) after a standardised training session conducted by an expert evaluator. Each dog was assessed by all three evaluators on the same day with both evaluator and limb test order randomised and testing sessions separated by 5 min. Mean ST values were averaged for all four limbs to produce a single value per dog for comparison between evaluators. Agreement between evaluators was determined using the intra-class correlation coefficient (ICC; two-way model for consistency, single measures). ICC across all three evaluators was 0.48, indicating moderate agreement. Moderate interobserver agreement is not sufficient to support the use of this technique in multi-center clinical trials, and our results underscore the importance of using a single evaluator for this QST technique until better agreement can be demonstrated.

Photonic crystal laser with mode selective mirrors.

The mini-stopband (MSB) of a W3 line-defect photonic crystal waveguide is used as a mirror for a GaAs based quantum-dot laser. Single mode, continuous-wave lasing is demonstrated for broad area lasers up to a current of 125 mA (2.7 x laser threshold), which demonstrates the high degree of mode selectivity of the MSB mirror. FDTD calculations indicate that optimisation of the mirror interface could lead to a further fourfold increase in reflectivity resulting in significantly reduced thresholds.

Prevention of cardiomyopathy in mouse models lacking the smooth muscle sarcoglycan-sarcospan complex.

Cardiomyopathy is a multifactorial disease, and the dystrophin-glycoprotein complex has been implicated in the pathogenesis of both hereditary and acquired forms of the disease. Using mouse models of cardiomyopathy made by ablating genes for components of the sarcoglycan complex, we show that long-term treatment with verapamil, a calcium channel blocker with vasodilator properties, can alleviate the severe cardiomyopathic phenotype, restoring normal serum levels for cardiac troponin I and normal cardiac muscle morphology. Interruption of verapamil treatment leads again to vascular dysfunction and acute myocardial necrosis, indicating that predilection for cardiomyopathy is a continuing process. In contrast, verapamil did not prevent cardiac muscle pathology in dystrophin-deficient mdx mice, which neither show a disruption of the sarcoglycan complex in vascular smooth muscle nor vascular dysfunction. Hence, our data strongly suggest that pharmacological intervention with verapamil merits investigation as a potential therapeutic option not only for patients with sarcoglycan mutations, but also for patients with idiopathic cardiomyopathy associated with myocardial ischemia not related to atherosclerotic coronary artery disease.