We evaluated the contribution of p38 mitogen-activated protein kinase and the events upstream/downstream of p38 leading to dopaminergic neuronal death. We utilized MN9D cells and primary cultures of mesencephalic neurons treated with 6-hydroxydopamine. Phosphorylation of p38 preceded apoptosis and was sustained in 6-hydroxydopamine-treated MN9D cells. Cotreatment with PD169316 (an inhibitor of p38) or expression of a dominant negative p38 was neuroprotective in death induced by 6-hydroxydopamine. The superoxide dismutase mimetic and the nitric oxide chelator blocked 6-hydroxydopamine-induced phosphorylation of p38, suggesting a role for superoxide anion and nitric oxide in eliciting a neurotoxic signal by activating p38. Following 6-hydroxydopamine treatment, inhibition of p38 prevented both caspase-8-and -9-mediated apoptotic pathways as well as generation of truncated Bid. Consequently, 6-hydroxydopamine-induced cell death was rescued by blockading activation of caspase-8 and -9. In primary cultures of mesencephalic neurons, the phosphorylation of p38 similarly appeared in tyrosine hydroxylase-positive, dopaminergic neurons after 6-hydroxydopamine treatment. This neurotoxin-induced phosphorylation of p38 was inhibited in the presence of superoxide dismutase mimetic or nitric oxide chelator. Co-treatment with PD169316 deterred 6-hydroxydopamine-induced loss of dopaminergic neurons and activation of caspase-3 in these neurons. Furthermore, inhibition of caspase-8 and -9 significantly rescued 6-hydroxydopamine-induced loss of dopaminergic neurons. Taken together, our data suggest that superoxide anion and nitric oxide induced by 6-hydroxydopamine initiate the p38 signal pathway leading to activation of both mitochondrial and extramitochondrial apoptotic pathways in our culture models of Parkinson's disease. Parkinson's disease (PD)1 is a common neurodegenerative disorder characterized by a progressive loss of dopaminergic neurons in the substantia nigra. Although its precise etiology is unknown, such factors as oxidative stress, impairment of mitochondrial respiration, and abnormal protein aggregation may play roles in its pathogenesis (1, 2). Although the role of apoptosis in the process of dopaminergic neuronal death has been highlighted in studies using postmortem brains and experimental models of PD, other evidence implicates both apoptosis and non-apoptotic death in PD (3). Regardless, it is not clearly understood which signals may be involved in determining the mode of dopaminergic neuronal death.Among the upstream signals leading to neuronal degeneration, one may include the stress-activated protein kinases. These are c-Jun N-terminal kinases (JNK) and p38 kinases, which are activated in response to various stimuli and are potent effectors of neuronal apoptosis (4). Most interesting, the phosphorylated forms of JNK and p38 are expressed in postmortem brains of PD (5). Moreover, evidence from experimental models of PD has implicated JNK in the process of dopaminergic neuronal death. For example, activation ...

Albeit a similar safety profile with low clinical event rates, transcatheter aortic valve replacement with the ACURATE neo valve resulted in lower transvalvular gradients and consequently less prosthesis-patient mismatch compared with the SAPIEN 3 in patients with small annulus. These results emphasize the need of careful prosthesis selection in each individual patient.

Live, attenuated Salmonella Typhimurium vaccine candidate expressing BCSP31, Omp3b, and SOD proteins of Brucella abortus was constructed. Thirty BALB/c mice were divided equally into three groups, Group A, were intraperitoneally (IP) inoculated with 100 μl of approximately 1.2 × 106 colony-forming units (CFUs)/ml of the Salmonella containing vector only in 100 μl as a control. And groups B and C mice were orally and IP immunized with approximately 1.2 × 109 CFU/ml of the mixture of three delivery strains in 10 μl and IP immunized with approximately 1.2 × 106 CFU/ml of the mixture in 100 μl, respectively. The serum IgG, TNF-α and IFN-γ concentrations in groups B (except Omp3b) and C were significantly higher than those in group A. Following challenge with B. abortus strain 544; challenge strain was detected <103 CFU from the spleen of all mice of group C. These results suggest that IP immunization with the mixture of the vaccine candidate can induce immune responses, and can effectively protect mice against brucellosis.

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Phase-contrast magnetic resonance imaging (PC-MRI) offers a range of surrogate markers to quantify the hemodynamic changes associated with chronic thromboembolic pulmonary hypertension (CTEPH). Our aim was to noninvasively monitor effects of pulmonary vascular remodeling before and after endarterectomy (PEA) in patients with CTEPH by using PC-MRI. Fifty-seven consecutive patients (mean age 56.7 ± 16, 28 female) underwent PC-MRI before and after PEA as part of their peri-operative routine workup. Pulmonary artery (PA) maximum flow velocity (maxV), acceleration time/ejection time (AT/ET), distensibility [(PA maximum area - PA minimum area)/PA minimum area], mid-systolic flow deceleration (notch), and the timing of deceleration (notch ratio) were recorded. Mean PA pressure was obtained from standard right heart catheter procedures. maxV and AT/ET were decreased before PEA and significantly improved afterwards (60.8 ± 16 vs. 73.8 ± 19 cm/s, p = 0.007; 0.32 ± 0.06 vs. 0.36 ± 0.09, p = 0.0015). Surprisingly, distensibility did not change significantly (30 ± 19 vs. 26 ± 12%, p = 0.11). Forty-five patients (78%) had a systolic notch before PEA that persisted in only 10 (18%; p = 0.00001). Among patients with a persisting notch, the notch ratio did not significantly increase (1.3 ± 0.2 vs. 1.6 ± 1.5, p = 0.32). Our data show early PA reverse remodeling after PEA. Flow velocities increase while PA flow wave reflections represented by mid-systolic flow deceleration are abolished. In some patients a mid-systolic notch persists, suggesting increased downstream resistance as a consequence of small vessel arteriopathy.

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