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Studies on leptospirosis : clinical aspects and pathophysiology - Chapter 7: Long pentraxin PTX3 is associated with mortality and disease severity in severe leptospirosis.

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UvA-DARE is a service provided by the library of the University of Amsterdam (https://dare.uva.nl)

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Studies on leptospirosis : clinical aspects and pathophysiology

Wagenaar, J.F.P.

Publication date

2010

Link to publication

Citation for published version (APA):

Wagenaar, J. F. P. (2010). Studies on leptospirosis : clinical aspects and pathophysiology.

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