An animal model of chronic inflammatory pain: pharmacological and temporal differentiation from acute models.

Clinically, inflammatory pain is far more persistent than that typically modelled pre-clinically, with the majority of animal models focussing on short-term effects of the inflammatory pain response. The large attrition rate of compounds in the clinic which show pre-clinical efficacy suggests the need for novel models of, or approaches to, chronic inflammatory pain if novel mechanisms are to make it to the market. A model in which a more chronic inflammatory hypersensitivity phenotype is profiled may allow for a more clinically predictive tool. The aims of these studies were to characterise and validate a chronic model of inflammatory pain. We have shown that injection of a large volume of adjuvant to the intra-articular space of the rat knee results in a prolonged inflammatory pain response, compared to the response in an acute adjuvant model. Additionally, this model also results in a hypersensitive state in the presence and absence of inflammation. A range of clinically effective analgesics demonstrate activity in this chronic model, including morphine (3mg/kg, t.i.d.), dexamethasone (1mg/kg, b.i.d.), ibuprofen (30mg/kg, t.i.d.), etoricoxib (5mg/kg, b.i.d.) and rofecoxib (0.3-10mg/kg, b.i.d.). A further aim was to exemplify the utility of this chronic model over the more acute intra-plantar adjuvant model using two novel therapeutic approaches; NR2B selective NMDA receptor antagonism and iNOS inhibition. Our data shows that different effects were observed with these therapies when comparing the acute model with the model of chronic inflammatory joint pain. These data suggest that the chronic model may be more relevant to identifying mechanisms for the treatment of chronic inflammatory pain states in the clinic.     

Abnormal movements in Rett syndrome are present before the regression period: a case study.

The suspicion of a diagnosis of Rett syndrome (RTT) is based on clinical criteria that are often not present in the first two stages of the disease, as many of its symptoms will appear at a later age. This sometimes postpones the genetic diagnosis and an early clinical intervention. We present the case of 19-months-old girl who came to the consultation because of an arrest of psychomotor development noticed 5 months earlier without change in sleep pattern, behavior, or social communication. In the observation of 1 hour videotape, she presented subtle stereotypic movements of the face and hands as well as repetitive dystonic posturing of her limbs. A genetic test confirmed the diagnosis of RTT, showing a truncating mutation in the MECP2 gene (R270X). This case confirms that stereotypic movement anomalies, albeit infrequent and subtle, are already present before the regression stage and while maintaining prehension and that, in addition, repetitive dystonic postures may occur. Recognition of these early movement disorders will improve clinicians' ability to perform an earlier diagnosis of RTT.     

Is chronic nitrate therapy associated with a different clinical presentation of acute coronary syndrome?

BACKGROUND: Nitrate therapy can induce ischemic preconditioning with a consequent increase in tolerance to ischemia. In the context of acute coronary syndromes (ACS), nitrates may result in a different presentation. with greater protection. OBJECTIVES: To investigate in a population of patients with ACS whether previous chronic use of nitrates results in a different presentation of ACS. METHODS: We studied 287 patients (65 +/- 13 years, 66% male) admitted to our department in the first six months of 2005 with ACS (with and without ST-segment elevation). Of these, 8% were under nitrate therapy at the time of admission. In this group, 27% presented ACS without ST-segment elevation, while in the group without nitrates this value was 58% (p = 0.005). By univariate analysis, the use of nitrates was a predictor of the preferential occurrence of non-ST-segment elevation ACS (OR 0.27, 95% CI 0.10-0.71). After correction for the potential influence of variables (age, gender, previous revascularization and smoking) by multivariate logistic regression, nitrate therapy remained a borderline predictor of clinical presentation as non-ST-segment elevation ACS (OR 0.37, 95% CI 0.13-1.04, p = 0.059). CONCLUSIONS: Previous use of nitrates was associated with a tendency to present as non-ST-segment elevation ACS. This finding may be explained by the hypothesis that nitrates induce pharmacological preconditioning, reducing the transmural extent of myocardial infarction.     

Clinical performance of non-contact tonometry by Reichert AT550® in glaucomatous patients

Measuring intraocular pressure (IOP) by non-contact tonometry (NCT) has been demonstrated to be a valid and reliable technique to be used in primary eye care; it is easier to use, it does not transmit infectious diseases, and it is not necessary to use anaesthetic or staining eye drops. Recently, a new NCT device has showed an excellent level of agreement with Goldmann tonometry, but there are no records of its performance in glaucomatous eyes. To rectify this, IOP was measured in twenty-two patients (44 eyes) receiving medical treatment to control elevated IOP, with AT550 and Goldmann tonometry. Mean values of IOP were 18.98 +/- 2.77 and 19.08 +/- 3.02 mmHg using Goldmann and AT550, respectively. Plots of differences against means displayed good agreement (mean difference +/- limits of agreement, -0.09 +/- 3.30); this value was not significantly different from zero (t-test for dependent samples, p = 0.709). In conclusion, IOP values as measured with the AT550 NCT are clinically comparable with those obtained with Goldmann tonometry in glaucomatous patients. This validates this NCT not only for screening of IOP but to follow-up glaucomatous patients with a rapid, non-invasive method.     

Pallidotomy in Parkinson's disease improves single-joint, repetitive, ballistic movements, but fails to modify multijoint, repetitive, gestural movements.

We studied 12 non-demented PD patients in on state before and 3 months after posteroventral pallidotomy (PVP), in order to evaluate the effects of surgery upon an unconstrained, multijoint skilled movement as well as a single joint, repetitive, ballistic movement. A Selspot II System was used for three-dimensional data acquisition, processing and reconstruction of limb trajectories. Specific wrist kinematic features of spatial accuracy (linearity and planarity), temporal attributes (acceleration and velocity), spatiotemporal relationships (velocity-curvature coupling), and joint kinematic variables (relationships between wrist and elbow velocities and relative arm angle amplitudes) for each cycle of movement were graphically and numerically analysed. QMC was applied to single joint, repetitive, ballistic movements. QMC significantly improved after PVP (P < 0.0006). However, wrist as well as joint kinematic variables of the gestural movements failed to change significantly after PVP. The lack of improvement of the kinematic abnormalities of the gestural movement in PD patients would indicate that they are unrelated to the basic motor deficit; most likely they are the result of a disruption of a complex of sensorimotor integration processes due to abnormal parieto-frontal basal ganglia interaction.     

Effects of a toxin from the mucus of the caribbean sea anemone (Bunodosoma granulifera) on the ionic currents of single ventricular mammalian cardiomyocytes

The effects were studied of a toxin (Bainh) isolated from the secretion of the Caribbean sea anemone Bunodosoma granulifera on electrical and mechanical activities of rat ventricular muscle. The effects on the ionic currents of single rat and dog ventricular cardiomyocytes were studied using the whole-cell recording patch-clamp technique. In the concentration range from 1 to 10 mg/ml, Bainh increased the force of contraction and induced an increase in action potential duration of ventricular multicellular preparations. In single cardiomyocytes, at concentrations up to 10 mg/ml Bainh showed no significant effects on the sodium current. However, at 0.5–1 mg/ml it increased the L-type Ca current (I_CaL) by 25–50%. This increase in I_CaL was not voltage dependent and was reversible after washout. The transient outward current was not significantly affected by Bainh (1–10 mg/ml). In this concentration range, Bainh markedly (≈75%) increased the inward-going rectifier current, I_K1. This effect that was not voltage dependent and was fully reversible upon returning to control solution. It is suggested that these effects on ionic currents could explain the positive inotropic action of Bainh on cardiac multicellular preparations.     

Serotonergic receptors in the brain of in utero undernourished rats

In this study, we report that 5-HT(1A) receptors are already present in fractions of axonal growth cones, from the normal rat fetal brain (E-17). Also, in utero undernourished (UN) rat pups at birth show a noteworthy enhancement in the B(max) of [3H]5-hydroxytryptamine (5-HT) and [3H]8-hydroxy-(2-N,N-dipropilamin)-tetralin (([3H])8-OH-DPAT), in the brainstem and cerebral cortex up to the second week after birth. Afterwards, there is a significant decrease in the binding of these ligands. [125I]Cyanopindolo binding in the cerebral cortex only showed a decrease in the same period. An elevation of brain serotonin in both regions was also present. These findings together, suggest that the mechanisms of regulation of serotonergic receptors' expression during the period studied, may not depend on the amount of neurotransmitter in the synaptic cleft, because in the early UN brain it would be expected only a lower receptor's density due to the chronic serotonin increase. On this basis, we propose that developmental activation of brain serotonin biosynthesis observed in early UN animals may disrupt the mechanism regulating the expression of 5-HT receptors during development.