Morphological characteristics of motor neurons do not determine their relative susceptibility to degeneration in a mouse model of severe spinal muscular atrophy

Spinal muscular atrophy (SMA) is a leading genetic cause of infant mortality, resulting primarily from the degeneration and loss of lower motor neurons. Studies using mouse models of SMA have revealed widespread heterogeneity in the susceptibility of individual motor neurons to neurodegeneration, but the underlying reasons remain unclear. Data from related motor neuron diseases, such as amyotrophic lateral sclerosis (ALS), suggest that morphological properties of motor neurons may regulate susceptibility: in ALS larger motor units innervating fast-twitch muscles degenerate first. We therefore set out to determine whether intrinsic morphological characteristics of motor neurons influenced their relative vulnerability to SMA. Motor neuron vulnerability was mapped across 10 muscle groups in SMA mice. Neither the position of the muscle in the body, nor the fibre type of the muscle innervated, influenced susceptibility. Morphological properties of vulnerable and disease-resistant motor neurons were then determined from single motor units reconstructed in Thy.1-YFP-H mice. None of the parameters we investigated in healthy young adult mice - including motor unit size, motor unit arbor length, branching patterns, motor endplate size, developmental pruning and numbers of terminal Schwann cells at neuromuscular junctions - correlated with vulnerability. We conclude that morphological characteristics of motor neurons are not a major determinant of disease-susceptibility in SMA, in stark contrast to related forms of motor neuron disease such as ALS. This suggests that subtle molecular differences between motor neurons, or extrinsic factors arising from other cell types, are more likely to determine relative susceptibility in SMA

Role of the mesoamygdaloid dopamine projection in emotional learning

Amygdala dopamine is crucially involved in the acquisition of Pavlovian associations, as measured via conditioned approach to the location of the unconditioned stimulus (US). However, learning begins before skeletomotor output, so this study assessed whether amygdala dopamine is also involved in earlier 'emotional' learning. A variant of the conditioned reinforcement (CR) procedure was validated where training was restricted to curtail the development of selective conditioned approach to the US location, and effects of amygdala dopamine manipulations before training or later CR testing assessed. Experiment 1a presented a light paired (CS+ group) or unpaired (CS- group) with a US. There were 1, 2 or 10 sessions, 4 trials per session. Then, the US was removed, and two novel levers presented. One lever (CR+) presented the light, and lever pressing was recorded. Experiment 1b also included a tone stimulus. Experiment 2 applied intra-amygdala R(+) 7-OH-DPAT (10 nmol/1.0 A mu l/side) before two training sessions (Experiment 2a) or a CR session (Experiment 2b). For Experiments 1a and 1b, the CS+ group preferred the CR+ lever across all sessions. Conditioned alcove approach during 1 or 2 training sessions or associated CR tests was low and nonspecific. In Experiment 2a, R(+) 7-OH-DPAT before training greatly diminished lever pressing during a subsequent CR test, preferentially on the CR+ lever. For Experiment 2b, R(+) 7-OH-DPAT infusions before the CR test also reduced lever pressing. Manipulations of amygdala dopamine impact the earliest stage of learning in which emotional reactions may be most prevalent

Branch Mode Selection during Early Lung Development

Many organs of higher organisms, such as the vascular system, lung, kidney, pancreas, liver and glands, are heavily branched structures. The branching process during lung development has been studied in great detail and is remarkably stereotyped. The branched tree is generated by the sequential, non-random use of three geometrically simple modes of branching (domain branching, planar and orthogonal bifurcation). While many regulatory components and local interactions have been defined an integrated understanding of the regulatory network that controls the branching process is lacking. We have developed a deterministic, spatio-temporal differential-equation based model of the core signaling network that governs lung branching morphogenesis. The model focuses on the two key signaling factors that have been identified in experiments, fibroblast growth factor (FGF10) and sonic hedgehog (SHH) as well as the SHH receptor patched (Ptc). We show that the reported biochemical interactions give rise to a Schnakenberg-type Turing patterning mechanisms that allows us to reproduce experimental observations in wildtype and mutant mice. The kinetic parameters as well as the domain shape are based on experimental data where available. The developed model is robust to small absolute and large relative changes in the parameter values. At the same time there is a strong regulatory potential in that the switching between branching modes can be achieved by targeted changes in the parameter values. We note that the sequence of different branching events may also be the result of different growth speeds: fast growth triggers lateral branching while slow growth favours bifurcations in our model. We conclude that the FGF10-SHH-Ptc1 module is sufficient to generate pattern that correspond to the observed branching modesComment: Initially published at PLoS Comput Bio

From presence to consciousness through virtual reality

Immersive virtual environments can break the deep, everyday connection between where our senses tell us we are and where we are actually located and whom we are with. The concept of 'presence' refers to the phenomenon of behaving and feeling as if we are in the virtual world created by computer displays. In this article, we argue that presence is worthy of study by neuroscientists, and that it might aid the study of perception and consciousness

Adverse childhood experiences and suicide attempts in morbidly obese adults

Introdução: As tentativas de suicídio surgem frequentemente associadas a problemas alimentares, tanto anorexia quanto bulimia. Do mesmo modo, tem-se verifi cado uma elevada ocorrência de suicídio entre obesos. Investigações têm mostrado que a adversidade na infância pode ser um fator de risco para as tentativas de suicídio. Objetivos: Caracterizar e compreender a relação entre experiências de adversidade na infância e tentativas de suicídio em 100 obesos mórbidos candidatos a cirurgia bariátrica. Métodos: Um total de 100 pacientes foram selecionados de setembro de 2007 a outubro de 2007 e de janeiro de 2008 a janeiro de 2009, sendo que 20 pacientes eram do sexo feminino. A média de idade era de 38,89±9,87 anos, e a média do peso máximo era de 136,43±14 kg. O Questionário da História de Adversidade na Infância foi utilizado para avaliar experiências adversas. Resultados: 88% dos pacientes relataram a existência de pelo menos uma experiência de adversidade na infância, e 25% relataram já ter realizado pelo menos uma tentativa de suicídio. A adversidade na infância esteve associada a um risco aumentado para realizar tentativas de suicídio (odds ratio = 2,026). Conclusão: Esses dados devem ser levados em consideração na avaliação e no acompanhamento desses pacientes.Introduction: Suicide attempts are often associated with eating disorders, both anorexia and bulimia. Likewise, a high incidence of suicide has been observed among obese patients. Previous studies have shown that adverse experiences in childhood may be a risk factor for suicide attempts. Objectives: To characterize and to understand the relationship between adverse experiences and suicide attempts in 100 morbidly obese patients referred for bariatric surgery. Methods: A total of 100 patients were selected from September 2007 to October 2007 and from January 2008 to January 2009. Of these, 20 patients were females. Mean age was 38.89±9.87 years, and mean maximum weight was 136.43±14 kg. The Portuguese version of the Family ACE (Adverse Childhood Experiences) Questionnaire was used to assess the occurrence of adverse events. Results: 88% of the patients reported the existence of at least one adverse experience in childhood, and 25% reported at least one previous suicide attempt. Adversity in childhood was associated with an increased risk for suicide attempts (odds ratio = 2.026). Conclusion: These data should be taken into account in the assessment and monitoring of these patients.Fundação para a Ciência e a Tecnologia (FCT); (SFRH/BD/37069/2007)

Relation between the Global Burden of Disease and Randomized Clinical Trials Conducted in Latin America Published in the Five Leading Medical Journals

Background: Since 1990 non communicable diseases and injuries account for the majority of death and disability-adjusted life years in Latin America. We analyzed the relationship between the global burden of disease and Randomized Clinical Trials (RCTs) conducted in Latin America that were published in the five leading medical journals.Methodology/Principal Findings: We included all RCTs in humans, exclusively conducted in Latin American countries, and published in any of the following journals: Annals of Internal Medicine, British Medical Journal, Journal of the American Medical Association, Lancet, and New England Journal of Medicine. We described the trials and reported the number of RCTs according to the main categories of the global burden of disease. Sixty-six RCTs were identified. Communicable diseases accounted for 38 (57%) reports. Maternal, perinatal, and nutritional conditions accounted for 19 (29%) trials. Non-communicable diseases represent 48% of the global burden of disease but only 14% of reported trials. No trial addressed injuries despite its 18% contribution to the burden of disease in 2000.Conclusions/Significance: A poor correlation between the burden of disease and RCTs publications was found. Non communicable diseases and injuries account for up to two thirds of the burden of disease in Latin America but these topics are seldom addressed in published RCTs in the selected sample of journals. Funding bodies of health research and editors should be aware of the increasing burden of non communicable diseases and injuries occurring in Latin America to ensure that this growing epidemic is not neglected in the research agenda and not affected by publication bias

Effectiveness of mobile-phone short message service (SMS) reminders for ophthalmology outpatient appointments: Observational study

Abstract Background Non-attendance for hospital outpatient appointments is a significant problem in many countries. It causes suboptimal use of clinical and administrative staff and financial losses, as well as longer waiting times. The use of Short Message Service (SMS) appointment reminders potentially offers a cost-effective and time-efficient strategy to decrease non-attendance and so improve the efficiency of outpatient healthcare delivery. Methods An SMS text message was sent to patients with scheduled appointments between April and September 2006 in a hospital ophthalmology department in London, reminding them of their appointments. This group acted as the intervention group. Controls were patients with scheduled ophthalmology appointments who did not receive an SMS or any alternative reminder. Results During the period of the study, 11.2% (50/447) of patients who received an SMS appointment reminder were non-attenders, compared to 18.1% (1720/9512) who did not receive an SMS reminder. Non-attendance rates were 38% lower in patients who received an SMS reminder than in patients who did not receive a reminder (RR of non-attendance = 0.62; 95% CI = 0.48 – 0.80). Conclusion The use of SMS reminders for ophthalmology outpatient appointments was associated with a reduction of 38% in the likelihood of patients not attending their appointments, compared to no appointment reminder. The use of SMS reminders may also be more cost-effective than traditional appointment reminders and require less labour. These findings should be confirmed with a more rigorous study design before a wider roll-out.</p

Molecular and cellular mechanisms underlying the evolution of form and function in the amniote jaw.

The amniote jaw complex is a remarkable amalgamation of derivatives from distinct embryonic cell lineages. During development, the cells in these lineages experience concerted movements, migrations, and signaling interactions that take them from their initial origins to their final destinations and imbue their derivatives with aspects of form including their axial orientation, anatomical identity, size, and shape. Perturbations along the way can produce defects and disease, but also generate the variation necessary for jaw evolution and adaptation. We focus on molecular and cellular mechanisms that regulate form in the amniote jaw complex, and that enable structural and functional integration. Special emphasis is placed on the role of cranial neural crest mesenchyme (NCM) during the species-specific patterning of bone, cartilage, tendon, muscle, and other jaw tissues. We also address the effects of biomechanical forces during jaw development and discuss ways in which certain molecular and cellular responses add adaptive and evolutionary plasticity to jaw morphology. Overall, we highlight how variation in molecular and cellular programs can promote the phenomenal diversity and functional morphology achieved during amniote jaw evolution or lead to the range of jaw defects and disease that affect the human condition