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After opening some tile sources and then clearing cache and doing a gc.collect(), some file handles were still open (this can be checked via /proc//fd). This cures the test cases I've found except for nd2 files that start to open and then fail. I filed an issue with the nd2 reader about that.
The bioformats reader also has issues in this regard, which probably has something to do with the java library (not the python side of things).