Outline
The article by Ross et al is the first to discuss calcium-independent PLA2 in the context of schizophrenia, and implies that these 2 fields of inquiry are linked in some biologically relevant manner. However, it is a daunting task to search the existing literature to assess the potential relevance of regulators or effects of PLA2 that may have already been discussed in print in some context other than schizophrenia. We have developed a computer-assisted strategy (ARROWSMITH), [3] which has proved useful in identifying promising new directions for research in several previous cases [3-6] and which we have applied to the problem posed above.
MEDLINE was searched to create a local computer file of records containing the phrases "phospholipase A2 " and "calcium-independent," and a file of titles containing the word "schizophrenia." All words and phrases were identified that were common to the 2 sets of titles; "noninteresting" words were excluded with a precompiled 5000-word stop-list plus manual editing, leaving a set of 38 "X-terms." For each X-term, a printed display was prepared of titles in which PLA2 and X co-occurred; this list was juxtaposed with titles in which X and schizophrenia co-occurred. This format allowed us to assess quickly whether X might represent a plausible biological link between calcium-independent PLA2 and schizophrenia.
Among the output, an article by Kuo et al [7] particularly stands out: a model of chronic oxidative stress in rats, produced by combined vitamin E and selenium deficiency for 6 weeks, leads to an elevation of calcium-independent PLA2 in cytosol of lung, liver, and (marginally) heart. Citation analysis of this article revealed the existence of a follow-up article, [8] published in a journal not indexed by MEDLINE, showing that elevation of calcium-independent PLA2 also occurs in spleen. [8] This elevation is selective in that it is not observed in the kidney and is not accompanied by an increase in calcium-dependent PLA2 levels in several of the tissues examined. The elevated calcium-independent PLA2 level is reversed within a week of dietary repletion. [8]
That chronic oxidative stress causes an elevation of calcium-independent PLA2 within several tissues is intriguing, because several independent lines of evidence suggest that a state of chronic oxidative stress may occur in schizophrenia. [1,9,10] Therefore, we suggest that it would be worthwhile to examine rats, treated as in Kuo et al, [7,8] to learn if calcium-independent PLA2 becomes elevated in the serum when assayed as in Ross et al. [1] If so, then one will have a convenient animal model for identifying the cellular source(s) of serum calcium-independent PLA2, for examining whether calcium-independent PLA2 is elevated in brain as well, and for studying both the mechanisms and the functional consequences of the elevations. Conversely, if such an animal model is validated, one would predict that treating schizophrenic patients with antioxidants should reverse the elevation in serum PLA2.
The 2 articles identified by our search were in nutritional journals (which are not generally read by psychiatrists, neuroscientists, or enzymologists) and had not been cited by any review articles. Yet ARROWSMITH found them and highlighted their potential relevance, illustrating its power to identify articles that cannot be found readily by conventional literature searches. Investigators are invited to carry out ARROWSMITH searches on topics of their own interest, on our free experimental Web site located at http://kiwi.uchicago.edu.
Department of Psychiatry (M/C 912); University of Illinois at Chicago; 1601 W Taylor St; Chicago, IL 60612
Division of the Humanities; University of Chicago; 1010 E 59th St; Chicago, IL 60637
REFERENCES^
1. Ross BM, Hudson C, Erlich J, Warsh JJ, Kish SJ. Increased phospholipid breakdown in schizophrenia: evidence for the involvement of a calcium-independent phospholipase A2. Arch Gen Psychiatry. 1997;54:487-494. [Fulltext Link] [Medline Link] [BIOSIS Previews Link] [Context Link]
2. Balsinde J, Dennis EA. Function and inhibition of intracellular calcium-independent phospholipase A2. J Biol Chem. 1997;272:16069-16072. [Medline Link] [BIOSIS Previews Link] [Context Link]
3. Swanson DR, Smalheiser NR. An interactive system for finding complementary literatures: a stimulus to scientific discovery. Artif Intell. 1997;91:183-203. [Context Link]
4. Smalheiser NR, Swanson DR. Assessing a gap in the biomedical literature: magnesium deficiency and neurologic disease. Neurosci Res Commun. 1994;15:1-9. [BIOSIS Previews Link] [Context Link]
5. Smalheiser NR, Swanson DR. Indomethacin and Alzheimer's disease. Neurology. 1996;46:583. [Fulltext Link] [Medline Link] [BIOSIS Previews Link] [Context Link]
6. Smalheiser NR, Swanson DR. Linking estrogen to Alzheimer's disease: an informatics approach. Neurology. 1996;46:809-810. [Medline Link] [BIOSIS Previews Link] [Context Link]
7. Kuo C-F, Cheng S, Burgess JR. Deficiency of vitamin E and selenium enhances calcium-independent phospholipase A2 activity in rat lung and liver. J Nutrition. 1995;125:1419-1429. [Context Link]
8. Burgess JR, Kuo C-F. Increased calcium-independent phospholipase A2 activity in vitamin E and selenium-deficient rat lung, liver, and spleen cytosol is time-dependent and reversible. J Nutr Biochem. 1996;7:366-374. [BIOSIS Previews Link] [Context Link]
9. Horrobin DF, Glen AIM, Vaddadi K. The membrane hypothesis of schizophrenia. Schiz Res. 1994;13:195-207. [Context Link]
10. McCreadie RG, MacDonald E, Wiles D, Campbell G, Paterson JR. Plasma lipid peroxide and serum vitamin E levels in patients with and without tardive dyskinesia, and in normal subjects. Br J Psychiatry. 1995;167:610-617. [Medline Link] [BIOSIS Previews Link] [Context Link]
Calcium; Phospholipase A2; Phospholipases A; Schizophrenia
Accession Number: 00000756-199808000-00011