BOLD-fMRI of PTZ-induced seizures in rats

PURPOSE: To develop a non-invasive method for exploring seizure initiation and propagation in the brain of intact experimental animals. METHODS: We have developed and applied a model-independent statistical method--Hierarchical Cluster Analysis (HCA)--for analyzing BOLD-fMRI data following administration of pentylenetetrazol (PTZ) to intact rats. HCA clusters voxels into groups that share similar time courses and magnitudes of signal change, without any assumptions about when and/or where the seizure begins. RESULTS: Epileptiform spiking activity was monitored by EEG (outside the magnet) following intravenous PTZ (IV-PTZ; n=4) or intraperitoneal PTZ administration (IP-PTZ; n=5). Onset of cortical spiking first occurred at 29+/-16 s (IV-PTZ) and 147+/-29 s (IP-PTZ) following drug delivery. HCA of fMRI data following IV-PTZ (n=4) demonstrated a single dominant cluster, involving the majority of the brain and first activating at 27+/-23s. In contrast, IP-PTZ produced multiple, relatively small, clusters with heterogeneous time courses that varied markedly across animals (n=5); activation of the first cluster (involving cortex) occurred at 130+/-59 s. With both routes of PTZ administration, the timing of the fMRI signal increase correlated with onset of EEG spiking. CONCLUSIONS: These experiments demonstrate that fMRI activity associated with seizure activity can be analyzed with a model-independent statistical method. HCA indicated that seizure initiation in the IV- and IP-PTZ models involves multiple regions of sensitivity that vary with route of drug administration and that show significant variability across animal subjects. Even given this heterogeneity, fMRI shows clear differences that are not apparent with typical EEG monitoring procedures, in the activation patterns between IV and IP-PTZ models. These results suggest that fMRI can be used to assess different models and patterns of seizure activation.     

The autoinflammatory side of recurrent pericarditis: Enlightening the pathogenesis for a more rational treatment

Recurrent pericarditis (RP) is a troublesome and debilitating complication of acute pericarditis. Although the etiopathogenesis of this condition remains unknown, an intricate overlap of autoimmune and autoinflammatory pathways has been hypothesized to explain its beginning and recurrence over time. The majority of cases are defined as “idiopathic”, reflecting our awkwardness to unravel the intimate mechanisms of RP. Given the possible occurrence of anti-nuclear, anti-heart and anti-intercalated disk antibodies as well as the association with peculiar human leukocyte antigen haplotypes, an autoimmune contribution has been claimed to specify the nature of RP. However, the most innovative pathogenic scenario of RP has been conferred to the innate immune system, mainly involving neutrophils and macrophages that produce a large amount of interleukin (IL)-1 via inflammasome activation. The clinical resemblance of RP with autoinflammatory diseases that may be marked by symptomatic serositis, high fevers and strikingly increased inflammatory parameters further suggests a similar inflammasome-mediated pathogenesis. Aspirin or non-steroidal anti-inflammatory drugs (NSAIDs) remain the mainstay of therapy in RP, whereas colchicine is recommended on top of standard anti-inflammatory therapy, due to its role in inhibiting the IL-1 converting enzyme (caspase 1) within the inflammasome as well as the release of additional pro-inflammatory mediators and reactive oxygen species. With regard to treatment of RP refractory to NSAIDs and colchicine, blockade of IL-1 is the most relevant advance achieved in the last decade: the outstanding effect of the short-acting IL-1 receptor antagonist anakinra has been first recognized in the pediatric population, giving a proof of its practical feasibility. Over a more recent time, a growing experience with anakinra deriving from both large and small studies has further confirmed that RP might be regarded as an IL-1-mediated disease. This review aims to provide a contemporary insight into the mechanisms leading to RP as well as into the most recent literature data showing the beneficial approach originating from IL-1 blockade in this intriguing disorder.     

Using patient-reported outcome measures to estimate cost-effectiveness of hip replacements in English hospitals

Objective

To estimate the average cost per quality adjusted life year (QALY) gained from hip surgery, and to examine the variation in that between hospitals.

Design

The transformation of patient-reported outcome measures (EQ-5D data) into QALYs, covering 25,463 NHS patient episodes between April 2009 and August 2010 from hospitals in England, using a model of future health change arising from a hip operation compared to a counterfactual of no operation. Hospital-level costs for hip procedures from the National Reference Costs data-set was used to calculate the hospitals'' cost per QALY.

Setting

English hospitals treating NHS-funded patients undergoing hip replacement.

Participants

NHS-funded patients undergoing primary hip replacement.

Main outcome measure

Cost per QALY.

Results

Assuming some degradation in patients’ health over the lifetime of the hip prosthesis, average health gain arising from a hip operation was 2.77 QALYs. For procedures paid for by the NHS but carried out in the independent sector the average gain was 2.97 QALYs. Average NHS hospital hip procedure costs were estimated to be £5844. The unweighted average cost per QALY for NHS hospitals was £2128. There were significant variations in cost per QALY between hospitals; most of this variation appears to be driven by variations in cost, not QALYs.

Conclusions

Using the new patient-assessed health-related quality of life data combined with routine hospital-level cost data it is possible to estimate a procedure-based measure of efficiency for hospitals. The fact that variations in cost per QALY are strongly driven by variations in cost suggests that further work is needed to investigate the causes of cost variations per se – especially the quality of routine NHS cost data.