Neuroanatomy of the pain system and of the pathways that modulate pain

We review many of the recent findings concerning mechanisms and pathways for pain and its modulation, emphasizing sensitization and the modulation of nociceptors and of dorsal horn nociceptive neurons. We describe the organization of several ascending nociceptive pathways, including the spinothalamic, spinomesencephalic, spinoreticular, spinolimbic, spinocervical, and postsynaptic dorsal column pathways in some detail and discuss nociceptive processing in the thalamus and cerebral cortex. Structures involved in the descending analgesia systems, including the periaqueductal gray, locus ceruleus, and parabrachial area, nucleus raphe magnus, reticular formation, anterior pretectal nucleus, thalamus and cerebral cortex, and several components of the limbic system are described and the pathways and neurotransmitters utilized are mentioned. Finally, we speculate on possible fruitful lines of research that might lead to improvements in therapy for pain.     

P-glycoprotein function involves conformational transitions detectable by differential immunoreactivity

The MDR1 P-glycoprotein (Pgp), a member of the ATP-binding cassette family of transporters, is a transmembrane ATPase efflux pump for various lipophilic compounds, including many anti-cancer drugs. mAb UIC2, reactive with the extracellular moiety of Pgp, inhibits Pgp-mediated efflux. UIC2 reactivity with Pgp was increased by the addition of several Pgp-transported compounds or ATP-depleting agents, and by mutational inactivation of both nucleotide-binding domains (NBDs) of Pgp. UIC2 binding to Pgp mutated in both NBDs was unaffected in the presence of Pgp transport substrates or in ATP-depleted cells, whereas the reactivities of the wild-type Pgp and Pgps mutated in a single NBD were increased by these treatments to the level of the double mutant. These results indicate the existence of different Pgp conformations associated with different stages of transport-associated ATP hydrolysis and suggest trapping in a transient conformation as a mechanism for antibody-mediated inhibition of Pgp.     

Acute hemorrhagic pulmonary infarction and necrotizing pneumonia in horses: 21 cases (1967-1993)

Specimens of formalin-fixed, paraffin-embedded non-small-cell lung carcinomas (NSCLCs; n = 187) were analysed immunohistochemically for expression of cyclin A. The analysis was intended to determine whether cyclin A has additional prognostic value for predicting patients' survival and drug response. Of the 187 NSCLCs, 141 cases (75%) showed expression of cyclin A. Patients with cyclin A-positive carcinomas had significantly shorter median survival times than patients with cyclin A-negative carcinomas (79 vs 129 weeks, P = 0.045). Similar results were obtained with more homogeneous groups of patients: patients with only T3 tumours, patients with epidermoid carcinomas and patients with lymph node involvement. The clinical parameters (age, stage, histology, extent of tumour size, lymph node involvement) had no influence on expression of cyclin A. A direct correlation between cyclin A and the proportion of S-phase cells (P = 0.08) and an inverse relationship between cyclin A and the proportion of G0/G1-phase cells (P = 0.04) were found. Furthermore, a significant correlation between the expression of cyclin A and the response of NSCLC to doxorubicin in vitro was detected (P = 0.026).     

Voltammetric behaviour of iron in cement II: effect of sodium chloride and corrosion inhibitor additions

A method for studying the behaviour of iron reinforcement in cured Portland cement paste using linear sweep cyclic voltammetry is described. The use of this method is demonstrated for thein situ study of: (i) the formation of passive films on iron embedded in cement; (ii) the NaCl-induced disruption of these passive films; and, (iii) the protection of passive films on iron in salt-contaminated cement pastes by corrosion inhibitors. Disruption of the passivity was observed upon potential cycling following immersion of cement-embedded iron electrodes for 24h in solutions containing as little as 0.1M NaCl. Corrosion inhibitors such as sodium nitrite, potassium chromate and sodium benzoate all had some beneficial effect in maintaining the passivity of the iron electrodes in the presence of potentially damaging concentrations of NaCl. Of these inhibitors, sodium nitrite was the most effective at the levels used in this study.     

The effects of D-23129, a new experimental anticonvulsant drug, on neurotransmitter amino acids in the rat hippocampus in vitro

Recent literature continues to promote the early use of disease-modifying antirheumatic drugs (DMARDs), especially the less toxic agents such as hydroxychloroquine. Reports of combination DMARD treatments have been disappointing, and careful attention must be paid to clinical trial design if the efficacy of combination therapies is to be established. Methotrexate retains its prominent role, and its mechanism of action has been the subject of many reports; its toxicity remains the most common reason for treatment termination. Guidelines for monitoring hepatic toxicity of methotrexate have been published and may help reduce the need for invasive biopsy procedures. Significant risk factors for methotrexate pulmonary toxicity remain difficult to identify. Large placebo-controlled studies of both sulfasalazine and hydroxychloroquine have been reported and have demonstrated the efficacy of these agents in the treatment of early rheumatoid arthritis. Awareness of drug-toxicity profiles is important for physicians who prescribe these agents.     

Cerebral protection by intermittent reperfusion during temporary focal ischemia in the rat

Temporary arterial occlusion has been routinely used as an adjunct in intracranial aneurysm surgery. This has commonly been performed using a protocol of multiple short periods of occlusion alternating with periods of restoration of normal circulation. Recently, the logical basis of this method has come under scrutiny. There is extensive experimental evidence to suggest that repetitive, brief periods of global ischemia may cause more severe cerebral injury than an equivalent single period of global ischemia. Only recently has this issue begun to be addressed with regard to focal ischemia. Hence, despite the common use of temporary clipping, little experimental data are available regarding the ischemic consequences of temporary arterial occlusion with periods of reperfusion versus uninterrupted temporary occlusion. To investigate this issue, a protocol of occlusion/reperfusion that simulates the temporal profile that occurs during surgery was performed in a rat model of focal ischemia. Sixteen anesthetized Sprague-Dawley rats were divided into two groups. The animals in Group I underwent 60 minutes of uninterrupted middle cerebral artery occlusion and the animals in Group II were subjected to six separate 10-minute occlusion periods with 5 minutes of reperfusion between occlusions. Histopathological analysis was performed 72 hours postischemia. Group I had significantly increased mean infarction volumes (50.0 +/- 12.1 mm3) compared to Group II (8.7 +/- 3.1 mm3) (p = 0.008). Injuries in Group I occurred in both the cortex and striatum, whereas Group II showed only striatal injuries. Furthermore, the extent of the injuries in Group II was less severe, characterized by ischemic neuronal injury rather than frank infarction. The results indicate that intermittent reperfusion is neuroprotective during temporary focal ischemia and support the hypothesis that intermittent reperfusion is beneficial if temporary clipping is required during aneurysm repair.     

Accuracy of duplex ultrasound in evaluating carotid artery anatomy before endarterectomy

PURPOSE: Anatomic features, such as a high carotid bifurcation (< 1.5 cm from the angle of the mandible), excessive distal extent of plaque (> 2.0 cm above the carotid bifurcation), or a small diameter (< or = 0.5 cm) redundant or kinked internal carotid artery can complicate carotid endarterectomy. In the past, arteriography was the only preoperative study capable of imaging these features. This study assessed the ability of duplex ultrasound to evaluate their presence before surgery. METHODS: A consecutive series of 20 patients who underwent 21 carotid endarterectomies had preoperative duplex ultrasound evaluations of these anatomic features. These evaluations were correlated with operative measurements from an observer blinded to the duplex findings. RESULTS: The mean difference between duplex and operative measurements for the distance between the carotid bifurcation and the angle of the mandible, the distal extent of plaque, and the internal carotid artery diameter was 0.9 cm, 0.3 cm, and 0.8 mm, respectively. The correlation coefficient between the two methods was 0.86, 0.75, and 0.59, respectively. Duplex ultrasound predicted a high carotid bifurcation, excessive distal extent of plaque, or a redundant or kinked internal carotid artery with 100% sensitivity (p < 0.05, p < 0.01, and p < 0.001, respectively). The sensitivity of duplex ultrasound in predicting a small internal carotid artery diameter was 80%. The specificity of duplex ultrasound for predicting excessive distal extent of plaque, small internal carotid artery diameter, high carotid bifurcation, and a coiled or kinked carotid artery was 92%, 56%, 100%, and 100%, respectively. CONCLUSION: Duplex ultrasound can predict the presence of anatomic features that may complicate carotid endarterectomy. Preoperative duplex imaging of these features may be helpful in patients who undergo carotid endarterectomy without preoperative arteriography.