Peripheral inflammation exacerbates α-synuclein toxicity and neuropathology in Parkinson's models.

AIMS: Parkinson's disease and related disorders are devastating neurodegenerative pathologies. Since α-synuclein was identified as a main component of Lewy bodies and neurites, efforts have been made to clarify the pathogenic mechanisms of α-synuclein's detrimental effects. α-synuclein oligomers are the most harmful species and may recruit and activate glial cells. Inflammation is emerging as a bridge between genetic susceptibility and environmental factors co-fostering Parkinson's disease. However, direct evidence linking inflammation to the harmful activities of α-synuclein oligomers or to the Parkinson's disease behavioural phenotype is lacking. METHODS: To clarify whether neuroinflammation influences Parkinson's disease pathogenesis, we developed: (i) a 'double-hit' approach in C57BL/6 naive mice where peripherally administered lipopolysaccharides were followed by intracerebroventricular injection of an inactive oligomer dose; (ii) a transgenic 'double-hit' model where lipopolysaccharides were given to A53T α-synuclein transgenic Parkinson's disease mice. RESULTS: Lipopolysaccharides induced a long-lasting neuroinflammatory response which facilitated the detrimental cognitive activities of oligomers. LPS-activated microglia and astrocytes responded differently to the oligomers with microglia activating further and acquiring a pro-inflammatory M1 phenotype, while astrocytes atrophied. In the transgenic 'double-hit' A53T mouse model, lipopolysaccharides aggravated cognitive deficits and increased microgliosis. Again, astrocytes responded differently to the double challenge. These findings indicate that peripherally induced neuroinflammation potentiates the α-synuclein oligomer's actions and aggravates cognitive deficits in A53T mice. CONCLUSIONS: The fine management of both peripheral and central inflammation may offer a promising therapeutic approach to prevent or slow down some behavioural aspects in α-synucleinopathies.

TLR3 preconditioning induces anti-inflammatory and anti-ictogenic effects in mice mediated by the IRF3/IFN-ß axis.

Activation of Toll-like receptor 3 (TLR3) was previously shown to contribute to the generation of epileptic seizures in rodents by evoking a proinflammatory response in the forebrain. This suggests that TLR3 blockade may provide therapeutic effects in epilepsy. We report that brain activation of TLR3 using the synthetic receptor ligand Poly I:C may also result in remarkable dose- and time-dependent inhibitory effects on acute seizures in mice without inducing inflammation. These inhibitory effects are associated with reduced neuronal excitability in the hippocampus as shown by a decrease in the population spike amplitude of CA1 pyramidal neurons following Schaffer collaterals stimulation. TLR3 activation which results in seizure inhibition does not evoke NF-kB-dependent inflammatory molecules or morphological activation of glia, however, it induces the alternative interferon (IFN) regulatory factor (IRF)-3/IFN-ß signaling pathway. IFN-ß reproduced the inhibitory effects of Poly I:C on neuronal excitability in hippocampal slices. Seizure inhibition attained with activation the TLR3-IRF3/IFN-ß axis should be carefully considered when TLR3 are targeted for therapeutic purposes.

Predicting no-reflow phenomenon prior to primary percutaneous coronary intervention using a novel probability risk score derived from clinical and angiographic parameters.

OBJECTIVE: We aimed to create a clinically usable probability risk score for prediction of no-reflow (NRF) phenomenon prior to primary percutaneous coronary intervention (PPCI). PATIENTS AND METHODS: This single-center and retrospective study included 1254 patients with acute ST-segment elevation myocardial infarction (STEMI) who underwent PPCI. Patients were randomly assigned into two groups in the ratio 2:1, the derivation dataset (n=840) and validation dataset (n=414). Independent predictors of NRF were identified and combined to create a prediction model using univariate and multivariate regression analysis in the derivation dataset. The risk score was tested and validated by calculating area under the receiver operating characteristic (ROC) curves in the derivation and validation datasets, respectively. RESULTS: Five significant, independent predictors of NRF were identified: age ≥ 65 years (odds ratio [OR]: 2.473, 95% confidence interval [CI]: 0.389-1.484, p < 0.01), heart rate ≥ 89 bpm (odds ratio [OR]: 1.622, 95% confidence interval [CI]: 0.024-0.945, p < 0.05), Killip class ≥ II (odds ratio [OR]: 1.914, 95% confidence interval [CI]: 0.024-1.306, p < 0.01), total ischemic time ≥ 268 min (odds ratio [OR]: 2.652, 95% confidence interval [CI]: 0.493-1.565, p < 0.01), and thrombus burden G≥4 (odds ratio [OR]: 8.351, 95% confidence interval [CI]: 0.344-15.901, p < 0.01). The risk score was created combining these predictors with assigned points. The overall score ranged from 0 to 17 points. The optimal cutoff value of the risk score was 11 points (area under curve [AUC]: 0.772, 95% confidence interval [CI]: 0.729-0.815, sensitivity 71.21%, specificity 70.34%, positive predictive value 30.92%, negative predictive value 92.91%, p < 0.001). The ROC curve for the validation group showed good discriminant power. CONCLUSIONS: We developed a novel risk score based on five clinical and angiographic parameters, which might be a useful clinical tool for prediction of NRF in STEMI patients prior to PPCI with an acceptable accuracy.

[Myomectomy by vaginal route].

Myomectomy by vaginal route is the least invasive of all methods for myoma removal. Compared to classical, abdominal myomectomy, it has numerous advantages, especially in cases of fundal and posterior wall myomas, but still it is relatively rarely performed. This study provides an analysis of operative and postoperative course of patients subjected to myomectomy by vaginal route in the period from 01/01/2003 to 01/11/2005 as well as the corresponding control group of patients which had undergone classical, abdominal myomectomy. The study points out to significance and advantages of application of surgical technique for removal of myoma through the posterior wall of the vagina as opposed to classical, abdominal myomectomy. Transvaginal myomectomy eliminates trauma of laparotomy, intraoperative blood loss is reduced, postoperative complications are down to minimum, postoperative recovery is shorter, and so is the number of days spent in hospital. Thus, by performing this type of surgery, a positive cost-benefit effect is obtained not only for the patient but for health authorities as well.