Effects of the polycyclic aromatic hydrocarbon heterocycles, carbazole and dibenzothiophene, on in vivo and in vitro CYP1A activity and polycyclic aromatic hydrocarbon-derived embryonic deformities

Heterocyclic derivatives of polycyclic aromatic hydrocarbons (PAHs) are often significant components of environmental contaminant mixtures; however, their contribution to the toxicity of these mixtures is not well characterized. These heterocycles commonly co-occur in PAH mixtures, which contain agonists for the aryl hydrocarbon receptor (AHR). Our goal for these studies was to explore the effects of two PAH heterocycles, carbazole (CB) and dibenzothiophene (DBT), alone and in combination with a PAH-type agonist for the AHR (beta-naphthoflavone [BNF]) on AHR-mediated cytochrome P4501A (CYP1A) activity and on fish embryotoxicity. Embryos of Fundulus heteroclitus were exposed to CB or DBT, with and without coexposure to BNE Carbazole alone slightly induced, whereas DBT alone slightly reduced, in ovo CYP1A-mediated ethoxyresorufin-O-deethylase (EROD) activity compared to control values. However, exposure to CB or DBT reduced in ovo EROD activity in embryos coexposed to BNE Carbazole and DBT were characterized in vitro as noncompetitive CYP1A inhibitors. Carbazole and DBT enhanced the embryotoxicity of BNF, although neither compound was embryotoxic by itself. The co-occurrence of CB and DBT with PAH-type AHR inducers in contaminated ecosystems may increase the toxicity of PAH-type AHR agonists in these settings and may need to be considered when estimating the embryotoxicity of PAH mixtures.     

Sustained attention in children and adolescents after traumatic brain injury: relation to severity of injury, adaptive functioning, ADHD and social background

Primary objective: To examine the relationship of child and family psychosocial variables and traumatic brain injury (TBI) severity as it relates to sustained attention (the Paediatric Assessment of Cognitive Efficiency, PACE).

Research design: Forty-two children and adolescents were recruited and participated in a 2 year longitudinal study to evaluate sustained attention using the computerized testing metric, PACE. More specifically, errors of omission (inattention) and commission (impulsiveness) were measured.

Main outcomes and results: Significant improvement on inattention and impulsiveness were observed over time. High pre-injury psychosocial adversity and low pre-injury adaptive functioning significantly predicted a greater number of inattention errors. Severity of injury predicted the reduction of impulsiveness. Moreover, omission errors immediately after TBI predicted later secondary attention-deficit/hyperactivity disorder (SADHD, ADHD that emerges after TBI).

Conclusions: Based on these findings, it is important to consider pre-injury child and family psychosocial characteristics in addition to severity of injury when predicting outcome of TBI in children.     

Sustained benefits of infliximab therapy for dermatologic and articular manifestations of psoriatic arthritis: results from the infliximab multinational psoriatic arthritis controlled trial (IMPACT)

OBJECTIVE: To investigate the efficacy and tolerability of infliximab therapy for the articular and dermatologic manifestations of active psoriatic arthritis (PsA). METHODS: One hundred four patients with PsA in whom prior therapy with at least 1 disease-modifying antirheumatic drug (DMARD) had failed were recruited into this investigator-initiated, multicenter, randomized, double-blind, placebo-controlled clinical trial. During the initial blinded portion of the study, patients received infusions of infliximab (5 mg/kg) or placebo at weeks 0, 2, 6, and 14. After week 16, patients initially assigned to receive placebo crossed over to receive infliximab 5 mg/kg every 8 weeks through week 50, while patients initially randomized to infliximab continued to receive active treatment at the same dose through week 50. The primary efficacy outcome was achievement of the American College of Rheumatology 20% criteria for improvement in rheumatoid arthritis (ACR20) at week 16. Additional predefined clinical efficacy assessments included the Psoriasis Area and Severity Index (PASI) score, the ACR50 and ACR70 criteria, the Disease Activity Score in 28 joints, the Health Assessment Questionnaire, ratings of enthesitis and dactylitis, and the Psoriatic Arthritis Response Criteria score. RESULTS: The proportion of infliximab-treated patients who achieved an ACR20 response at week 16 (65%) was significantly higher than the proportion of placebo-treated patients who achieved this response (10%). In addition, 46% of infliximab-treated patients achieved an ACR50 response, and 29% achieved an ACR70 response; no placebo-treated patient achieved these end points. Among patients who had PASI scores of >/=2.5 at baseline, 68% of infliximab-treated patients achieved improvement of >/=75% in the PASI score at week 16 compared with none of the placebo-treated patients. Continued therapy with infliximab resulted in sustained improvement in articular and dermatologic manifestations of PsA through week 50. The incidence of adverse events was similar between the treatment groups. CONCLUSION: Therapy with infliximab at a dose of 5 mg/kg significantly improved the signs and symptoms of arthritis, psoriasis, dactylitis, and enthesitis in patients with active PsA that had been resistant to DMARD therapy. With continued infliximab treatment, benefits were sustained through 50 weeks. The benefit-to-risk ratio appeared favorable in this study population.     

Outcome-Parameter bei Psoriasisarthritis

The most important and most commonly occurring form of psoriasis is psoriasis vulgaris. In the specialism of rheumatology palmoplantar pustulosis is also important. The outcome is influenced mainly by how severe and how widespread the manifestations affecting the skin and nails are. All manifestations affecting the joints and occurring in association with psoriasis are subsumed under the term ‘psoriatic arthritis’ (PsA). Asymmetric oligoarthritis, enthesitis and inflammatory spinal manifestations are especially frequent. PsA is a rheumatic illness with widely varying clinical pictures, most patients having signs and symptoms resembling those of spondyloarthritides (SpA) and other features of rheumatoid arthritis (RA) and/or of arthrosis/osteoarthritis (OA). Clinical features that are particularly typical of PsA are ray-wise joint involvement, dactylitis and osteodestructive and osteoproliferative joint destruction. Dactylitis, asymmetric joint involvement and enthesitis also occur in other SpA. It is becoming increasingly important to define outcome parameters for use in PsA against the backdrop of new forms of treatment. In the case of clinical outcome basic distinctions must be made between clinical signs and symptoms, function and structure. In PsA the sometimes significant manifestations affecting skin and nails must also be considered. The outcome parameters used thus far have varied very widely. The extent and intensity of involvement of the peripheral joints and insertions of tendons and of spinal involvement are particularly important in PsA. In addition, functional impairments, quality of life and parameters concerned with work must be considered. There are hardly any measuring instruments specific to PsA; many have been developed and used primarily for SpA or RA.     

White Matter Lesions and Encephalopathy in Patients Treated For Primary Central Nervous System Lymphoma

A retrospective analysis of the clinical presentations and neuroimaging characteristics of 33 patients with a primary central nervous system lymphoma (PCNL) who received cranial radiotherapy was performed to assess incidence of and risk factors for radiation-induced encephalopathy. CT and MRI scans were revised by a neurologist and a radiologist in conference. White matter abnormalities before and after radiotherapy on the last scan before recurrence were quantified according to a semi-quantitative scale. All available medical records were retrieved and reviewed with respect to demographic and tumor-related variables, treatment modalities, disease-free and overall survival and clinical symptoms and signs of encephalopathy. CT and MRI scans showed severe white matter lesions in 75% of 20 patients and in 86% of patients aged more than 60 years. Forty percent of patients presented with new clinical signs of cognitive impairment a median of 14.5 months after initial diagnosis (8.5 months after radiotherapy). The risk of white matter lesions appeared greater in patients aged > 60 (RR 1.2, 95% CI = 0.8–2.0), in patients with prior white matter lesions (RR 1.3, 95% CI = 0.8–2.1) and in patients with multifocal cerebral lymphoma (RR 1.5, 95% CI = 1.0–2.1). In conclusion, the risk of white matter lesions and clinical symptoms and signs of encephalopathy is high in patients treated by radiotherapy for PCNL. The risk appears to be greatest in older patients, patients with multifocal tumor and in those with prior white matter lesions on CT or MRI.