Isolation of δ-missulenatoxin-Mb1a, the major vertebrate-active spider δ-toxin from the venom of Missulena bradleyi (Actinopodidae)

The present study describes the isolation and pharmacological characterisation of the neurotoxin δ-missulenatoxin-Mb1a (δ-MSTX-Mb1a) from the venom of the male Australian eastern mouse spider, Missulena bradleyi. This toxin was isolated using reverse-phase high-performance liquid chromatography and was subsequently shown to cause an increase in resting tension, muscle fasciculation and a decrease in indirect twitch tension in a chick biventer cervicis nerve-muscle bioassay. Interestingly, these effects were neutralised by antivenom raised against the venom of the Sydney funnel-web spider Atrax robustus. Subsequent whole-cell patch-clamp electrophysiology on rat dorsal root ganglion neurones revealed that δ-MSTX-Mb1a caused a reduction in peak tetrodotoxin (TTX)-sensitive sodium current, a slowing of sodium current inactivation and a hyperpolarising shift in the voltage at half-maximal activation. In addition, δ-MSTX-Mb1a failed to affect TTX-resistant sodium currents. Subsequent Edman degradation revealed a 42-residue peptide with unusual N- and C-terminal cysteines and a cysteine triplet (Cys14-16). This toxin was highly homologous to a family of δ-atracotoxins (δ-ACTX) from Australian funnel-web spiders including conservation of all eight cysteine residues. In addition to actions on sodium channel gating and kinetics to δ-ACTX, δ-MSTX-Mb1a caused significant insect toxicity at doses up to 2000 pmol/g. δ-MSTX-Mb1a therefore provides evidence of a highly conserved spider δ-toxin from a phylogenetically distinct spider family that has not undergone significant modification. © 2003 Published by Elsevier B.V. on behalf of the Federation of European Biochemical Societies

Treatment of Rat Spinal Cord Injury with the Neurotrophic Factor Albumin-Oleic Acid: Translational Application for Paralysis, Spasticity and Pain

Sensorimotor dysfunction following incomplete spinal cord injury (iSCI) is often characterized by the debilitating symptoms of paralysis, spasticity and pain, which require treatment with novel pleiotropic pharmacological agents. Previous in vitro studies suggest that Albumin (Alb) and Oleic Acid (OA) may play a role together as an endogenous neurotrophic factor. Although Alb can promote basic recovery of motor function after iSCI, the therapeutic effect of OA or Alb-OA on a known translational measure of SCI associated with symptoms of spasticity and change in nociception has not been studied. Following T9 spinal contusion injury in Wistar rats, intrathecal treatment with: i) Saline, ii) Alb (0.4 nanomoles), iii) OA (80 nanomoles), iv) Alb-Elaidic acid (0.4/80 nanomoles), or v) Alb-OA (0.4/80 nanomoles) were evaluated on basic motor function, temporal summation of noxious reflex activity, and with a new test of descending modulation of spinal activity below the SCI up to one month after injury. Albumin, OA and Alb-OA treatment inhibited nociceptive Tibialis Anterior (TA) reflex activity. Moreover Alb-OA synergistically promoted early recovery of locomotor activity to 50±10% of control and promoted de novo phasic descending inhibition of TA noxious reflex activity to 47±5% following non-invasive electrical conditioning stimulation applied above the iSCI. Spinal L4–L5 immunohistochemistry demonstrated a unique increase in serotonin fibre innervation up to 4.2±1.1 and 2.3±0.3 fold within the dorsal and ventral horn respectively with Alb-OA treatment when compared to uninjured tissue, in addition to a reduction in NR1 NMDA receptor phosphorylation and microglia reactivity. Early recovery of voluntary motor function accompanied with tonic and de novo phasic descending inhibition of nociceptive TA flexor reflex activity following Alb-OA treatment, mediated via known endogenous spinal mechanisms of action, suggests a clinical application of this novel neurotrophic factor for the treatment of paralysis, spasticity and pain

Do computerised clinical decision support systems for prescribing change practice? A systematic review of the literature (1990-2007)

Computerised clinical decision support systems (CDSSs) are used widely to improve quality of care and patient outcomes. This systematic review evaluated the impact of CDSSs in targeting specific aspects of prescribing, namely initiating, monitoring and stopping therapy. We also examined the influence of clinical setting (institutional vs ambulatory care), system- or user-initiation of CDSS, multi-faceted vs stand alone CDSS interventions and clinical target on practice changes in line with the intent of the CDSS. We searched Medline, Embase and PsychINFO for publications from 1990-2007 detailing CDSS prescribing interventions. Pairs of independent reviewers extracted the key features and prescribing outcomes of methodologically adequate studies (experiments and strong quasi-experiments). 56 studies met our inclusion criteria, 38 addressing initiating, 23 monitoring and three stopping therapy. At the time of initiating therapy, CDSSs appear to be somewhat more effective after, rather than before, drug selection has occurred (7/12 versus 12/26 studies reporting statistically significant improvements in favour of CDSSs on = 50% of prescribing outcomes reported). CDSSs also appeared to be effective for monitoring therapy, particularly using laboratory test reminders (4/7 studies reporting significant improvements in favour of CDSSs on the majority of prescribing outcomes). None of the studies addressing stopping therapy demonstrated impacts in favour of CDSSs over comparators. The most consistently effective approaches used system-initiated advice to fine-tune existing therapy by making recommendations to improve patient safety, adjust the dose, duration or form of prescribed drugs or increase the laboratory testing rates for patients on long-term therapy. CDSSs appeared to perform better in institutional compared to ambulatory settings and when decision support was initiated automatically by the system as opposed to user initiation. CDSSs implemented with other strategies such as education were no more successful in improving prescribing than stand alone interventions. Cardiovascular disease was the most studied clinical target but few studies demonstrated significant improvements on the majority of prescribing outcomes. Our understanding of CDSS impacts on specific aspects of the prescribing process remains relatively limited. Future implementation should build on effective approaches including the use of system-initiated advice to address safety issues and improve the monitoring of therapy

A narrative review on the similarities and dissimilarities between myalgic encephalomyelitis/chronic fatigue syndrome (me/cfs) and sickness behavior

It is of importance whether myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a variant of sickness behavior. The latter is induced by acute infections/injury being principally mediated through proinflammatory cytokines. Sickness is a beneficial behavioral response that serves to enhance recovery, conserves energy and plays a role in the resolution of inflammation. There are behavioral/symptomatic similarities (for example, fatigue, malaise, hyperalgesia) and dissimilarities (gastrointestinal symptoms, anorexia and weight loss) between sickness and ME/CFS. While sickness is an adaptive response induced by proinflammatory cytokines, ME/CFS is a chronic, disabling disorder, where the pathophysiology is related to activation of immunoinflammatory and oxidative pathways and autoimmune responses. While sickness behavior is a state of energy conservation, which plays a role in combating pathogens, ME/CFS is a chronic disease underpinned by a state of energy depletion. While sickness is an acute response to infection/injury, the trigger factors in ME/CFS are less well defined and encompass acute and chronic infections, as well as inflammatory or autoimmune diseases. It is concluded that sickness behavior and ME/CFS are two different conditions

O adolescente e o diabetes: uma experiência de vida El adolescente y la diabetes: una experiencia de vida Teenagers with type 1 diabetes mellitus: life experience report

OBJETIVO: Compreender como o adolescente com diabetes mellitus tipo I vivencia sua experiência de doença e como lida com esta situação no cotidiano. MÉTODOS: O Interacionismo Simbólico foi utilizado como referencial teórico e a Teoria Fundamentada nos Dados como o referencial metodológico da pesquisa. Participaram do estudo 10 adolescentes com diagnóstico de diabetes mellitus tipo 1 há mais de um ano. RESULTADOS: Foram identificados dois fenômenos explicativos da experiência: não sendo normal ter diabetes e sendo normal ter diabetes. CONCLUSÃO: Os dois fenômenos não são isolados ou excludentes para o mesmo adolescente, parecendo haver períodos ou fases em que os adolescentes identificam-se e vivenciam ora um fenômeno ora outro, com maior ou menor intensidade.<br>OBJETIVO: Comprender como el adolescente con diabetes mellitus tipo I experimenta su enfermedad y como lidia con esta situación en lo cotidiano. MÉTODOS: El Interaccionismo Simbólico fue utilizado como marco teórico y la Teoría Fundamentada en los Datos como el marco metodológico de la investigación. Participaron del estudio 10 adolescentes que tenían diagnóstico de diabetes mellitus tipo 1 hace más de un año. RESULTADOS: Fueron identificados dos fenómenos que explicaban la experiencia: no es normal tener diabetes y es normal tener diabetes. CONCLUSIÓN: Los dos fenómenos no están aislados o se excluyen mutuamente para el mismo adolescente, pareciendo haber períodos o fases en que los adolescentes se identifican y viven una vez un fenómeno y otra vez el otro, con mayor o menor intensidad.<br>PURPOSE: To understand the life experience of teenagers with type 1 diabetes mellitus and how they cope with the disease in daily life. METHODS: The symbolic interactionism was the theoretical perspective guiding the study. Grounded theory served as the method for using the empirical data. Participants consisted of 10 teenagers with type 1 diabetes mellitus over a year. RESULTS: Two phenomena explaining their life experience emerged: "Regarding having diabetes as being normal" and "regarding having diabetes as being abnormal." CONCLUSION: The two phenomena were not isolated or excluded from the life experience of the same teenager; there were phases in which the teenagers experienced one of the phenomena and vice-versa with greater or less intensity