ISIS 104838, a 2'-O-methoxyethyl (2'-MOE)-modified antisense oligonucleotide (ASO), causes a moderate, reproducible, dose-dependent, but selflimiting decrease in platelet (PLT) counts in monkeys and humans. To determine the etiology of PLT decrease in cynomolgus monkeys, a 12-week repeat dose toxicology study in 5 cynomolgus monkeys given subcutaneous injections of ISIS 104838 (30-60 mg/kg/week). Monkeys were also injected intravenously with 111Indium(In)-oxine-labeled PLTs to investigate PLT sequestration. In response to continued dosing, PLT counts were decreased by 50%-90% by day 30 in all monkeys. PLT decreases were accompanied by 2- to 4.5-fold increases in immunoglobulin M(IgM), which were typified by a 2- to 5-fold increase in antiplatelet factor 4 (antiPF4) IgM and antiPLT IgM, respectively. Monocyte chemotactic protein 1 increased upon dosing of ISIS 104838, concomitant with a 2- to 6-fold increase in monocyte-derived extracellular vesicles (EVs), indicating monocyte activation but not PLT activation. Despite a 2- to 3-fold increase in von Willebrand factor antigen in all monkeys following ASO administration, only 2 monkeys showed a 2- to 4-fold increase in endothelial EVs. Additionally, a ∼60 - 80%% increase in PLT sequestration in liver and spleen was also observed. Collectively, these results suggest the overall increase in total IgM, antiPLT IgM and/or antiPF4 IgM, in concert with monocyte activation contributed to increased PLT sequestration in spleen and liver, leading to decreased PLTs in peripheral blood.

French-Canadian composer Claude Vivier (1948–1983) is one of the few composers, perhaps the only one, to use an invented language throughout his entire compositional career. Vivier's use of what he called his langue inventée (‘invented language’) spanned the first vocal work in his catalogue – Ojikawa (1968) – to his final work, Glaubst du an die Unsterblichkeit der Seele (1983), completed only shortly before his murder in March 1983. Despite the pervasiveness of this technique – in fact, it is the only technique that remains a constant across all of Vivier's stylistic periods – relatively little attention has been given to the langue inventée in scholarship. This article presents a description of Vivier's langue inventée in three parts, beginning with a general introduction. The second part presents the langue inventée as a product of automatic writing and engages directly with Vivier's sketches to propose a method that Vivier likely used to write much of his langue inventée text. The final section of the article presents Vivier's langue inventée as a form of grammelot – a term revived by playwright, actor and director Dario Fo (1926–), which is associated with the dialect theatre of the Commedia dell'arte tradition. This article aims to demonstrate that Vivier's langue inventée is not a just a string of unintelligible nonsense syllables, but rather a very purposeful grammelot, freely composed in a two-stage approach to automatic writing, that reaches beyond linguistic semantics.

Claude Vivier’s homophonic treatment of combination tones—what he calledles couleurs—demands an extension of traditional methods of harmonic and spectral analysis. Incomplete explanations of this technique throughout the secondary literature further demand a revised and cohesive definition. To analyze all variations ofles couleurs, I developed the analytical concept of combination-tone classes (CTCs) and built upon Angela Lohri’s (2010) combination tone matrix to create a dynamic CTC matrix, from which CTC sets may be extracted. Intensive CTC set analysis reveals a definitive correlation between CTC set and formal sections in Vivier’s compositionBouchara. Although formally adjacent CTC sets are often markedly varied, all sets share a subset of lower-order CTCs, aiding in perception of spectral cohesion across formal boundaries. This analysis illuminates the interrelationships of CTC sets to their parent dyads, their orchestration, their playing technique, and form inBouchara. CTC set analysis is compared with Vivier’s sketches forBouchara, which suggest thatles couleurswere intended as integral components of the work’s musical structure.

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