Intra-arterial nitroglycerin as directed acute treatment in experimental ischemic stroke

BACKGROUND: Nitroglycerin (also known as glyceryl trinitrate (GTN)), a vasodilator best known for treatment of ischemic heart disease, has also been investigated for its potential therapeutic benefit in ischemic stroke. The completed Efficacy of Nitric Oxide in Stroke trial suggested that GTN has therapeutic benefit with acute (within 6 hours) transdermal systemic sustained release therapy. OBJECTIVE: To examine an alternative use of GTN as an acute therapy for ischemic stroke following successful recanalization. METHODS: We administered GTN IA following transient middle cerebral artery occlusion in mice. Because no standard dose of GTN is available following emergent large vessel occlusion, we performed a dose-response (3.12, 6.25, 12.5, and 25 µg/µL) analysis. Next, we looked at blood perfusion (flow) through the middle cerebral artery using laser Doppler flowmetry. Functional outcomes, including forced motor movement rotor rod, were assessed in the 3.12, 6.25, and 12.5 µg/µL groups. Histological analysis was performed using cresyl violet for infarct volume, and glial fibrillary activating protein (GFAP) and NeuN immunohistochemistry for astrocyte activation and mature neuron survival, respectively. RESULTS: Overall, we found that acute post-stroke IA GTN had little effect on vessel dilatation after 15 min. Functional analysis showed a significant difference between GTN (3.12 and 6.25 µg/µL) and control at post-stroke day 1. Histological measures showed a significant reduction in infarct volume and GFAP immunoreactivity and a significant increase in NeuN. CONCLUSIONS: These results demonstrate that acute IA GTN is neuroprotective in experimental ischemic stroke and warrants further study as a potentially new stroke therapy

Decision for reconstructive interventions of the upper limb in individuals with tetraplegia: the effect of treatment characteristics

Objective: To determine the effect of treatment characteristics on the\ud decision for reconstructive interventions for the upper extremities (UE) in\ud subjects with tetraplegia. - \ud Setting: Seven specialized spinal cord injury centres in the Netherlands. - \ud Method: Treatment characteristics for UE reconstructive interventions were\ud determined. Conjoint analysis (CA) was used to determine the contribution\ud and the relative importance of the treatment characteristics on the decision\ud for therapy. Therefore, a number of different treatment scenarios using these\ud characteristics were established. Different pairs of scenarios were presented\ud to subjects who were asked to choose the preferred scenario of each set. - \ud Results: forty nine subjects with tetraplegia with a stable C5, C6 or C7\ud lesion were selected. All treatment characteristics significantly influenced\ud the choice for treatment. Relative importance of treatment characteristics\ud were: intervention type (surgery or surgery with FES implant) 13%, number\ud of operations 15%, in patient rehabilitation period 22%, ambulant\ud rehabilitation period 9%, complication rate 15%, improvement of elbow\ud function 10%, improvement of hand function 15%. In deciding for therapy\ud 40% of the subjects focused on one characteristic. - \ud Conclusion: CA is applicable in Spinal Cord Injury medicine to study the\ud effect of health outcomes and non-health outcomes on the decision for\ud treatment. Non-health outcomes which relate to the intensity of treatment\ud are equally important or even more important than functional outcome in the\ud decision for reconstructive UE surgery in subjects with tetraplegia

How are falls and fear of falling associated with objectively measured physical activity in a cohort of community-dwelling older men?

BACKGROUND: Falls affect approximately one third of community-dwelling older adults each year and have serious health and social consequences. Fear of falling (FOF) (lack of confidence in maintaining balance during normal activities) affects many older adults, irrespective of whether they have actually experienced falls. Both falls and fear of falls may result in restrictions of physical activity, which in turn have health consequences. To date the relation between (i) falls and (ii) fear of falling with physical activity have not been investigated using objectively measured activity data which permits examination of different intensities of activity and sedentary behaviour. METHODS: Cross-sectional study of 1680 men aged 71-92 years recruited from primary care practices who were part of an on-going population-based cohort. Men reported falls history in previous 12 months, FOF, health status and demographic characteristics. Men wore a GT3x accelerometer over the hip for 7 days. RESULTS: Among the 12% of men who had recurrent falls, daily activity levels were lower than among non-fallers; 942 (95% CI 503, 1381) fewer steps/day, 12(95% CI 2, 22) minutes less in light activity, 10(95% CI 5, 15) minutes less in moderate to vigorous PA [MVPA] and 22(95% CI 9, 35) minutes more in sedentary behaviour. 16% (n = 254) of men reported FOF, of whom 52% (n = 133) had fallen in the past year. Physical activity deficits were even greater in the men who reported that they were fearful of falling than in men who had fallen. Men who were fearful of falling took 1766(95% CI 1391, 2142) fewer steps/day than men who were not fearful, and spent 27(95% CI 18, 36) minutes less in light PA, 18(95% CI 13, 22) minutes less in MVPA, and 45(95% CI 34, 56) minutes more in sedentary behaviour. The significant differences in activity levels between (i) fallers and non-fallers and (ii) men who were fearful of falling or not fearful, were mediated by similar variables; lower exercise self-efficacy, fewer excursions from home and more mobility difficulties. CONCLUSIONS: Falls and in particular fear of falling are important barriers to older people gaining health benefits of walking and MVPA. Future studies should assess the longitudinal associations between falls and physical activity

Binary credal classification under sparsity constraints.

Binary classification is a well known problem in statistics. Besides classical methods, several techniques such as the naive credal classifier (for categorical data) and imprecise logistic regression (for continuous data) have been proposed to handle sparse data. However, a convincing approach to the classification problem in high dimensional problems (i.e., when the number of attributes is larger than the number of observations) is yet to be explored in the context of imprecise probability. In this article, we propose a sensitivity analysis based on penalised logistic regression scheme that works as binary classifier for high dimensional cases. We use an approach based on a set of likelihood functions (i.e. an imprecise likelihood, if you like), that assigns a set of weights to the attributes, to ensure a robust selection of the important attributes, whilst training the model at the same time, all in one fell swoop. We do a sensitivity analysis on the weights of the penalty term resulting in a set of sparse constraints which helps to identify imprecision in the dataset

Safety of drug use in patients with a primary mitochondrial disease: An international Delphi-based consensus

Clinical guidance is often sought when prescribing drugs for patients with primary mitochondrial disease. Theoretical considerations concerning drug safety in patients with mitochondrial disease may lead to unnecessary withholding of a drug in a situation of clinical need. The aim of this study was to develop consensus on safe medication use in patients with a primary mitochondrial disease. A panel of 16 experts in mitochondrial medicine, pharmacology, and basic science from six different countries was established. A modified Delphi technique was used to allow the panellists to consider draft recommendations anonymously in two Delphi rounds with predetermined levels of agreement. This process was supported by a review of the available literature and a consensus conference that included the panellists and representatives of patient advocacy groups. A high level of consensus was reached regarding the safety of all 46 reviewed drugs, with the knowledge that the risk of adverse events is influenced both by individual patient risk factors and choice of drug or drug class. This paper details the consensus guidelines of an expert panel and provides an important update of previously established guidelines in safe medication use in patients with primary mitochondrial disease. Specific drugs, drug groups, and clinical or genetic conditions are described separately as they require special attention. It is important to emphasise that consensus-based information is useful to provide guidance, but that decisions related to drug prescribing should always be tailored to the specific needs and risks of each individual patient. We aim to present what is current knowledge and plan to update this regularly both to include new drugs and to review those currently included

What happens in the Lab: Applying Midstream Modulation to Enhance Critical Reflection in the Laboratory

In response to widespread policy prescriptions for responsible innovation, social scientists and engineering ethicists, among others, have sought to engage natural scientists and engineers at the ‘midstream’: building interdisciplinary collaborations to integrate social and ethical considerations with research and development processes. Two ‘laboratory engagement studies’ have explored how applying the framework of midstream modulation could enhance the reflections of natural scientists on the socio-ethical context of their work. The results of these interdisciplinary collaborations confirm the utility of midstream modulation in encouraging both first- and second-order reflective learning. The potential for second-order reflective learning, in which underlying value systems become the object of reflection, is particularly significant with respect to addressing social responsibility in research practices. Midstream modulation served to render the socio-ethical context of research visible in the laboratory and helped enable research participants to more critically reflect on this broader context. While lab-based collaborations would benefit from being carried out in concert with activities at institutional and policy levels, midstream modulation could prove a valuable asset in the toolbox of interdisciplinary methods aimed at responsible innovation

Structural and micro-anatomical changes in vertebrae associated with idiopathic-type spinal curvature in the curveback guppy model

Background: The curveback lineage of guppy is characterized by heritable idiopathic-type spinal curvature thatdevelops during growth. Prior work has revealed several important developmental similarities to the human idiopathicscoliosis (IS) syndrome. In this study we investigate structural and histological aspects of the vertebrae that areassociated with spinal curvature in the curveback guppy and test for sexual dimorphism that might explain a femalebias for severe curve magnitudes in the population.Methods: Vertebrae were studied from whole-mount skeletal specimens of curved and non-curved adult males andfemales. A series of ratios were used to characterize structural aspects of each vertebra. A three-way analysis of variancetested for effects of sex, curvature, vertebral position along the spine, and all 2-way interactions (i.e., sex and curvature,sex and vertebra position, and vertebra position and curvature). Histological analyses were used to characterize microarchitecturalchanges in affected vertebrae and the intervertebral region.Results: In curveback, vertebrae that are associated with curvature demonstrate asymmetric shape distortion,migration of the intervertebral ligament, and vertebral thickening on the concave side of curvature. There is sexualdimorphism among curved individuals such that for several vertebrae, females have more slender vertebrae than domales. Also, in the region of the spine where lordosis typically occurs, curved and non-curved females have a reducedwidth at the middle of their vertebrae, relative to males.Conclusions: Based on similarities to human spinal curvatures and to animals with induced curves, the concaveconvexbiases described in the guppy suggest that there is a mechanical component to curve pathogenesis incurveback. Because idiopathic-type curvature in curveback is primarily a sagittal deformity, it is structurally more similarto Scheuermann kyphosis than IS. Anatomical differences between teleosts and humans make direct biomechanicalcomparisons difficult. However, study of basic biological systems involved in idiopathic-type spinal curvature incurveback may provide insight into the relationship between a predisposing aetiology, growth, and biomechanics.Further work is needed to clarify whether observed sex differences in vertebral characteristics are related to the femalebias for severe curves that is observed in the population

A hypothetico-deductive approach to assessing the social function of chemical signalling in a non-territorial solitary carnivore

The function of chemical signalling in non-territorial solitary carnivores is still relatively unclear. Studies on territorial solitary and social carnivores have highlighted odour capability and utility, however the social function of chemical signalling in wild carnivore populations operating dominance hierarchy social systems has received little attention. We monitored scent marking and investigatory behaviour of wild brown bears Ursus arctos, to test multiple hypotheses relating to the social function of chemical signalling. Camera traps were stationed facing bear ‘marking trees’ to document behaviour by different age sex classes in different seasons. We found evidence to support the hypothesis that adult males utilise chemical signalling to communicate dominance to other males throughout the non-denning period. Adult females did not appear to utilise marking trees to advertise oestrous state during the breeding season. The function of marking by subadult bears is somewhat unclear, but may be related to the behaviour of adult males. Subadults investigated trees more often than they scent marked during the breeding season, which could be a result of an increased risk from adult males. Females with young showed an increase in marking and investigation of trees outside of the breeding season. We propose the hypothesis that females engage their dependent young with marking trees from a young age, at a relatively ‘safe’ time of year. Memory, experience, and learning at a young age, may all contribute towards odour capabilities in adult bears

The Search for Invariance: Repeated Positive Testing Serves the Goals of Causal Learning

Positive testing is characteristic of exploratory behavior, yet it seems to be at odds with the aim of information seeking. After all, repeated demonstrations of one’s current hypothesis often produce the same evidence and fail to distinguish it from potential alternatives. Research on the development of scientific reasoning and adult rule learning have both documented and attempted to explain this behavior. The current chapter reviews this prior work and introduces a novel theoretical account—the Search for Invariance (SI) hypothesis—which suggests that producing multiple positive examples serves the goals of causal learning. This hypothesis draws on the interventionist framework of causal reasoning, which suggests that causal learners are concerned with the invariance of candidate hypotheses. In a probabilistic and interdependent causal world, our primary goal is to determine whether, and in what contexts, our causal hypotheses provide accurate foundations for inference and intervention—not to disconfirm their alternatives. By recognizing the central role of invariance in causal learning, the phenomenon of positive testing may be reinterpreted as a rational information-seeking strategy