Comparison of tolerability and adverse symptoms in oxcarbazepine and carbamazepine in the treatment of trigeminal neuralgia and neuralgiform headaches using the Liverpool Adverse Events Profile (AEP)

Background Adverse effects of drugs are poorly reported in the literature . The aim of this study was to examine the frequency of the adverse events of antiepileptic drugs (AEDs), in particular carbamazepine (CBZ) and oxcarbazepine (OXC) in patients with neuralgiform pain using the psychometrically tested Liverpool Adverse Events Profile (AEP) and provide clinicians with guidance as to when to change management. Methods The study was conducted as a clinical prospective observational exploratory survey of 161 patients with idiopathic trigeminal neuralgia and its variants of whom 79 were on montherapy who attended a specialist clinic in a London teaching hospital over a period of 2 years. At each consultation they completed the AEP questionnaire which provides scores of 19–76 with toxic levels being considered as scores >45. Results The most common significant side effects were: tiredness 31.3 %, sleepiness 18.2 %, memory problems 22.7 %, disturbed sleep 14.1 %, difficulty concentrating and unsteadiness 11.6 %. Females reported significantly more side effects than males. Potential toxic dose for females is approximately 1200 mg of OXC and 800 mg of CBZ and1800mg of OXC and 1200 mg of CBZ for males. Conclusions CBZ and OXC are associated with cognitive impairment. Pharmacokinetic and pharmacodynamic differences are likely to be the reason for gender differences in reporting side effects. Potentially, females need to be prescribed lower dosages in view of their tendency to reach toxic levels at lower dosages. Side effects associated with AED could be a major reason for changing drugs or to consider a referral for surgical management

PGE2 Induces IL-6 in Orbital Fibroblasts through EP2 Receptors and Increased Gene Promoter Activity: Implications to Thyroid-Associated Ophthalmopathy

BACKGROUND: IL-6 plays an important role in the pathogenesis of Graves' disease and its orbital component, thyroid-associated ophthalmopathy (TAO). Orbital tissues become inflamed in TAO, a process in which prostanoids have been implicated. Orbital fibroblasts both generate and respond to PGE(2), underlying the inflammatory phenotype of these cells. METHODOLOGY/PRINCIPAL FINDINGS: Using cultured orbital and dermal fibroblasts, we characterized the effects of PGE(2) on IL-6 expression. We found that the prostanoid provokes substantially greater cytokine synthesis in orbital fibroblasts, effects that are mediated through cell-surface EP(2) receptors and increased steady-state IL-6 mRNA levels. The pre-translational up-regulation of IL-6 results from increased gene promoter activity and can be reproduced with the PKA agonist, Sp-cAMP and blocked by interrupting the PKA pathway. PGE(2)-induced production of cAMP in orbital fibroblasts was far greater than that in dermal fibroblasts, resulting from higher levels of adenylate cyclase. PGE(2) provokes CREB phosphorylation, increases the pCREB/CREB ratio, and initiates nuclear localization of the pCREB/CREB binding protein/p300 complex (CBP) preferentially in orbital fibroblasts. Transfection with siRNAs targeting either CREB or CBP blunts the induction of IL-6 gene expression. PGE(2) promotes the binding of pCREB to its target DNA sequence which is substantially greater in orbital fibroblasts. CONCLUSION/SIGNIFICANCE: These results identify the mechanism underlying the exaggerated induction of IL-6 in orbital fibroblasts and tie together two proinflammatory pathways involved in the pathogenesis of TAO. Moreover, they might therefore define an attractive therapeutic target for the treatment of TAO

Force Measurements of TCR/pMHC Recognition at T Cell Surface

The rupture forces and adhesion frequencies of single recognition complexes between an affinity selected peptide/MHC complex and a TCR at a murine hybridoma surface were measured using Atomic Force Microscopy. When the CD8 coreceptor is absent, the adhesion frequency depends on the nature of the peptide but the rupture force does not. When CD8 is present, no effect of the nature of the peptide is observed. CD8 is proposed to act as a time and distance lock, enabling the shorter TCR molecule to bridge the pMHC and have time to finely read the peptide. Ultimately, such experiments could help the dissection of the sequential steps by which the TCR reads the peptide/MHC complex in order to control T cell activation

Landform and surface attributes for prediction of rodent burrows in the Western Usambara Mountains, Tanzania

Previous studies suggest that rodent burrows, a proxy for rodent population are important for predicting plague risk areas. However, studies that link landform, surface attributes and rodent burrows in the Western Usambara Mountains in Tanzania are scanty. Therefore, this study was conducted in plague endemic area of the Western Usambara Mountains in northern, Tanzania, to explore the relationship between rodent burrows, and landform and surface attributes. The study was carried out in three areas corresponding to high (Lokome), medium (Lukozi) and low (Mwangoi) frequency of reported plague cases. Data were collected from 117, 200 and 170 observation sites for Lokome, Lukozi and Mwangoi, respectively using 100 m x 200 m quadrats. Remote sensing and field surveys were used to collect data on landform and surface attributes. Rodent burrows were surveyed and quantified by counting the number of burrows in 20m x 20m grids demarcated on the main 100m x 200m quadrats. The collected data were analysed in R software using boosted regression trees (BRT) technique. Rodent burrows were found at an elevation of above 1600m in the high and medium plague frequency landscapes. No burrows were found in the low plague frequency landscape situated below 1500m. BRT analysis shows a significant relationship between landform characteristics and rodent burrows in both high and medium plague frequency landscapes. Overall, elevation and hillshade are the most important determinants of rodent burrow distribution in the studied landscapes. It is concluded that in high altitudes, specific landform attributes (hill-shade, slope, elevation) and vegetation cover- favour rodent burrowingstatus: publishe

Thigh-length compression stockings and DVT after stroke

Controversy exists as to whether neoadjuvant chemotherapy improves survival in patients with invasive bladder cancer, despite randomised controlled trials of more than 3000 patients. We undertook a systematic review and meta-analysis to assess the effect of such treatment on survival in patients with this disease