Background Pathological and genetic evidence implicates toxic effects of aggregated α‐synuclein in the pathophysiology of neuronal dysfunction and degeneration in Parkinson's disease. Immunotherapy targeting aggregated α‐synuclein is a promising strategy for delaying disease progression. Objective This study (NCT02459886) evaluated the safety, tolerability, and pharmacokinetics of BIIB054, a human‐derived monoclonal antibody that preferentially binds to aggregated α‐synuclein, in healthy volunteers and participants with Parkinson's disease. Methods A total of 48 healthy volunteers (age 40–65, 19 women) and 18 Parkinson's disease participants (age 47–75, 5 women, Hoehn and Yahr stage ≤2.5) were in the study. Volunteers were enrolled into 6 single‐dose cohorts of BIIB054 (range 1–135 mg/kg) or placebo, administered intravenously; Parkinson's disease participants received a single dose of BIIB054 (15 or 45 mg/kg) or placebo. All participants were evaluated for 16 weeks with clinical, neuroimaging, electrocardiogram, and laboratory assessments. Serum and cerebrospinal fluid BIIB054 concentrations were measured. BIIB054/α‐synuclein complexes were measured in plasma. Results Most adverse events were mild and assessed by investigators as unrelated to the study drug. Pharmacokinetic parameters for volunteers and the Parkinson's disease participants were similar. BIIB054 serum exposure and maximum concentrations were dose proportional during the dose range studied. In volunteers and the Parkinson's disease participants, the serum half‐life of BIIB054 was 28 to 35 days; the cerebrospinal fluid–to‐serum ratio ranged from 0.13% to 0.56%. The presence of BIIB054/α‐synuclein complexes in plasma was confirmed; all Parkinson's disease participants showed almost complete saturation of the BIIB054/α‐synuclein complex formation. Conclusions BIIB054 has favorable safety, tolerability, and pharmacokinetic profiles in volunteers and Parkinson's disease participants, supporting further clinical development. © 2019 The Authors. Movement Disorders published by Wiley Periodicals, Inc. on behalf of International Parkinson and Movement Disorder Society.

We investigated the role of microparticles in vascular dysfunction of the multisystemic disorder of preeclampsia in women's omental arteries or mouse arteries. Preeclamptic women displayed increased circulating levels of leukocyte-and platelet-derived microparticles compared with healthy pregnant individuals. Microparticles from preeclamptic, but not healthy, pregnant women induced ex vivo vascular hyporeactivity to serotonin in human omental arteries and mouse aortas. Hyporeactivity was reversed by a nitric-oxide (NO) synthase inhibitor and associated with increased NO production. In the presence of a cyclooxygenase (COX)-2 inhibitor, serotonin-mediated contraction was partially reduced in arteries treated with healthy microparticles but was abolished after treatment with preeclamptic microparticles. This was associated with increased 8-isoprostane production. Preeclamptic microparticles induced up-regulation of inducible nitric-oxide synthase and COX-2 expression, evoked nuclear factor-B activation, and enhanced oxidative and nitrosative stress. Interestingly, the microparticles originating most probably from leukocytes were responsible for the COX-2 vasoconstrictor component of preeclamptic microparticles, whereas those of platelet origin were mainly involved in NO release. Moreover, vascular hyporeactivity was observed in arteries taken from mice treated in vivo with preeclamptic microparticles. This study demonstrates pathophysiological relevance and provides a paradoxical effect of preeclamptic microparticles associated with proinflammatory properties on vessels, leading to enhanced NO and superoxide anion levels and counteraction of increased COX-2 metabolites.

Maternal CD4 count is significantly and specifically associated with the risk of serious infections with encapsulated bacteria in HEU infants.

Preeclampsia is associated with an increase of circulating levels of microparticles (MPs), but their role in vascular dysfunction during the course of preeclampsia is not understood. Inasmuch as preeclampsia is a gestational disease, we tested the effect of MPs from preeclamptic women (PrMPs) and MPs from normal pregnant women (CMPs) on vessels from pregnant mice. We exposed aortic rings from pregnant mice to circulating levels of PrMPs or CMPs for 24 h and evaluated their response to serotonin (5-HT). PrMPs, but not CMPs, were able to induce hyporeactivity in response to 5-HT in aortas from pregnant mice. The nitric oxide (NO) synthase inhibitor N(G)-nitro-l-arginine strongly enhanced the response to 5-HT in PrMP-treated vessels but had no significant effect on CMP-treated vessels. The 5-HT-induced contraction in PrMP-treated vessels was completely abolished by the selective cyclooxygenase-2 (COX-2) inhibitor NS-398 but was only reduced in CMP-treated vessels, suggesting an increased participation of COX-2 vasoconstrictor products in the effect of PrMPs. Consistent with this hypothesis, PrMPs enhanced levels of 8-isoprostane and PGE(2) in vessels, despite reduction of thromboxane B(2). These results strengthen the main concept that MPs in preeclampsia could act as vectors to stimulate intracellular cascades in vascular cells, leading to an enhanced NO production to counteract increased COX-2 vasoconstrictor metabolites by taking into account pregnancy.

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