Joe Barcroft
email: barcroft@wustl.edu

Can writing a new word detract from learning it? More negative effects of forced output during vocabulary learning

This study examined effects of word writing on second language vocabulary learning. In two experiments, English-speaking learners of Spanish attempted to learn 24 Spanish nouns while viewing word-picture pairs. The participants copied 12 target words and wrote nothing for the other 12 target words being studied. Productive vocabulary learning on immediate and delayed (2 days later) measures was higher in the no-writing condition. These findings suggest that this type of forced output without access to meaning can detract from word learning by exhausting processing resources needed to encode novel lexical forms.

I Introduction

In evaluating the role of output (language produced by a learner) in second language (L2) acquisition, we may distinguish between output with access and output without access to meaning. Output with access refers to 'activating the lexical items and grammatical forms necessary to express particular meanings' (VanPatten, 2003: 63). Output without access, on the other hand, involves language production that does not require this type of activation, such as when a learner simply repeats something without intending to convey meaning. This study assessed the effects of copying target words (word writing) on L2 vocabulary learning. Word writing does not require access to meaning. From an input processing perspective, therefore, this type of output may decrease new word learning by exhausting cognitive processing resources that could be used to encode new word forms and establish new form-meaning mappings. This resource depletion for output (without access) hypothesis would gain support if word writing was found to produce less vocabulary learning than alternative no-writing conditions.

II Previous research on sentence writing, word writing and vocabulary learning

Previous studies have assessed effects of writing target words in sentences (sentence writing) and word writing on different measures of vocabulary learning. Both sentence writing and word writing involve output, but sentence writing involves tasks beyond word writing, such as elaborating on the meaning of target words, writing other words in each sentence, and processing for syntax. Previous studies have led to mixed conclusions about the effects of sentence writing. Some researchers found writing target words in sentences (Coomber et al., 1986) or essays (Laufer, 1997) to be more effective than alternative techniques. Others have found sentence writing to produce no effect (L1 study: Pressley et al., 1982) or negative effects (L1 studies: Pressley et al., 1982;McDaniel & Kearney, 1984;L2 studies: Barcroft, 1998;2000;2004;Folse, 1999) relative to alternative methods. Barcroft (2000;2002;2004) has maintained that these mixed findings may be attributed to particular operationalizations of 'deeper processing' in competing conditions, use of receptive versus productive measures, and other methodological limitations. Taking these considerations into account, the overall pattern of findings suggests that requiring learners to write target words in sentences can decrease their ability to learn those words by depleting processing resources that otherwise could be used to encode target word forms and establish form-meaning connections.

Research on word writing and L2 vocabulary learning has been limited. According to the resource depletion for output (RDO) hypothesis, copying a target word may exhaust processing resources that otherwise could be directed toward encoding the target word form and establishing new form-meaning mappings. The hypothesis does not exclude the possibility that producing a word to convey meaning may facilitate vocabulary learning. Self-generation of a target word presupposes prior exposure and input processing of the word, and studies have demonstrated positive effects for self-generation of target words on L2 vocabulary learning (Royer, 1973;McNamara and Healy, 1995). What remains in question is the effect of simply copying target words, a form of output without access. The RDO hypothesis predicts negative effects for this type of output.

Thomas and Dieter (1987) conducted a study on word writing among English-speaking learners of L2 French. The results of their first experiment indicated that word writing positively affected performance on an English-to-French translation task using scoring based on complete words (W) and complete words plus words with one letter wrong (Wϩ(W -1)) but not based on scoring that included word fragments (Wϩ(W -1)ϩF). The results of their second experiment revealed no significant differences using L2-to-L1 translation as a dependent measure. The results of their third experiment indicated higher free L2 recall in the writing group using W and Wϩ(W -1) scoring but not Wϩ(W -1)ϩF scoring. The researchers interpreted these results from the perspective that word writing facilitated learning complete orthographic representations.

III The present study

The present study consisted of two experiments on the effects of word writing on productive L2 vocabulary learning. These experiments differed from those of Thomas and Dieter in that they included:

• a within-subjects design; • a different presentation pattern during the learning phase (fewer repetitions); • more proficient learners; and • a different scoring protocol, designed to be highly sensitive to both full and partial productive word knowledge.

The present experiments approximated the experimental paradigm used by Barcroft (1998;2000;2004) in studies showing negative effects for sentence writing. When examined within this same type of experimental paradigm, what would be the effect (if any) of word writing?

1 Experiment 1

Experiment 1 assessed the effects of word writing during word-picture vocabulary learning using both immediate and delayed post-tests. If the results revealed a positive effect for word writing, they would provide evidence against the RDO hypothesis. If the results revealed a negative effect for word writing, they would provide evidence in favor of the RDO hypothesis.

a Method: Participants were 20 English-speaking L2 Spanish students in two second-semester Spanish classes at a large public university in the Midwestern United States. All participants met the following criteria:

• Their L1 was English.

• Spanish was not spoken regularly in their household.

• They did not correctly translate any of the target words on the pre-test.

Each participant attempted to learn 12 words in the word-writing condition and 12 words in the no-writing condition. To counterbalance learning conditions with word groups, 10 participants (Class 1) attempted to learn Words 1-12 in the no-writing condition and Words 13-24 in the word-writing condition, whereas the other 10 participants (Class 2) attempted to learn Words 1-12 in the word-writing condition and Words 13-24 in the word-writing condition.

The experiment included:

• a pre-test on which the 24 words appeared in reverse order from that of the learning phase (to avoid habituation while maintaining a structured order for counterbalancing); • a language background questionnaire; • a page with general instructions for the experiment;

• 24 numbered flash cards with each word written below its picture (for the learning phase); and 24 numbered flash cards with numbered pictures only (for testing);

• an audiotape with prerecorded beeps for presenting the stimuli in a time-controlled manner; overhead projectors on which the flashcards were placed so that they would appear on a television screen; • a word-writing sheet with instructions for the word-writing task and numbered boxes in which to write the words; and • two post-tests with instructions and 24 numbered spaces.

The 24 experimental words were the same concrete nouns as those used in sentence writing studies by Barcroft (1998;2000;2004) (e.g. serrote 'saw', regadera 'watering can', borla 'tassel'). Each of the two word groups contained 12 words. The average number of syllables in each word group was equal (M ϭ 3 for both word groups). The average number of letters in each word group was approximately equal (M ϭ 7.42 for Words 1-12, M ϭ 6.67 for Words 13-24). The 24 pictures of the target words were black-and-white drawings.

Data were collected in the participants' classrooms during class hours based on the following procedures. Each participant completed a language background questionnaire and the pre-test. Each participant read general instructions and was forewarned that in the testing phase they would be asked to write the target words in Spanish. Each word was presented twice for 6 seconds each time. Words 1-12 were presented twice. Words 13-24 were then presented in the same manner. In the word writing condition, participants were instructed to write each word once in the appropriate numbered box on the sheet. Immediately after the learning phase, Post-test 1 was administered. Participants were to write the target Spanish words as pictures only appeared on the screen. The same 24 pictures from the learning phase were presented for 12 seconds each in the same order as in the learning phase. After Post-test 1, the researcher did not inform the participants about a subsequent post-test. Two days later, the researcher returned to administer Post-test 2, which was the same as Post-test 1 except that it was labeled Post-test 2. After Post-test 2, the participants were asked to write whether they practiced or had any additional contact with the 24 Spanish words. If any participant indicated having practiced the target words beyond only 'thinking about them', their Post-test 2 scores were excluded from the dataset. Barcroft's (2000) lexical production scoring protocol (LPSP-written) was used to score both post-tests. A trained independent evaluator scored all post-tests. Blind scoring was used. LPSP-written scores reflect production of both fully and partially produced words (for details, see Barcroft, 2000;2004). In an effort to represent each participant's knowledge of target word forms as accurately as possible, some target words were scored in intended spaces when participants indicated with arrows that they had misplaced a response or series of responses or when it was judged to be the case based on response patterns on both post-tests during blind scoring. Scores for Words 1-12 and Words 13-24 were tabulated, providing totals for the no-writing and wordwriting conditions. Two subjects from Class 2 were not present for Post-test 2. The data provided by these participants and two randomly selected participants from Class 1 were excluded in order to maintain equal sizes at both post-tests.

b Results: LPSP-written scores were submitted to an analysis of variance (ANOVA). Condition (no writing, word writing) and time (immediate, 2 days later) were within-subject independent variables. The dependent variable was score. Alpha was set at 0.05 for the statistical analyses. Means for condition over time appear in Table 1. Results of the ANOVA revealed significant main effects for condition, F(1,15) ϭ 9.06, p ϭ 0.009, η 2 ϭ 0.377, and for time, F(1,15) ϭ 31.78, p Ͻ 0.001, η 2 ϭ 0.679. No other significant main effects or interactions were revealed. Consistent with the RDO hypothesis, the results indicated that word writing had a negative effect on productive L2 vocabulary learning. This negative effect maintained over time. Experiment 2 was a partial replication of Experiment 1 with a larger sample, participants from a different university, presentation of stimuli using a computer-based presentation program, and provisions for the participants to cover words that they had written previously during the learning phase (using a piece of construction paper). This final provision was included to control for the possibility that the appearance of the previously written words within the participants' field of vision in Experiment 1 might have caused confusion between different target word forms and referents. Additionally, during the testing phase of Experiment 2, the order of two consecutive target words (18. asa 'handle' and 19. sacudidor 'feather duster') was reversed from the order in which those two words appeared during the learning phase. This difference was consistent across both learning conditions. The extent to which the participants did or did not invert those two particular words on their post-tests was analysed to explore the extent to which the participants' performance on the post-tests reflected learning formmeaning connections between the target words and their referents as opposed to learning a particular presentation order. Other differences in Experiment 2 are described in the following sections.

a Method: Forty-six Spanish students in four second-semester Spanish classes at a private university in the Midwestern United States participated. All met the same criteria as in Experiment 1. The experimental materials in Experiment 2 were similar to those in Experiment 1, except that a computer presentation program was used to present instructions and the stimuli. The experimental words were the same as in Experiment 1. Data collection procedures followed those of Experiment 1 except that for the writing condition the participants were provided with sheets of construction paper to cover all previously written words on their word-writing sheets. Scoring procedures were the same as those used in Experiment 1.

b Results: The data were analysed as in Experiment 1, except for one additional analysis. Cases in which participants did or did not invert the consecutive target words asa 'handle' and sacudidor 'feather duster' were noted, totaled, and reported as results. Means for condition over time appear in Table 2. Results of the ANOVA revealed significant main effects for condition, F(1,45) ϭ 10.43, p ϭ 0.002, η 2 ϭ 0.188, and for time, F (1,45) ϭ 99.80, p Ͻ 0.001, η 2 ϭ 0.689. No other significant main effects or interactions emerged. Consistent with RDO hypothesis, the results of Experiment 2 indicated that word writing had a negative effect on productive L2 vocabulary learning. This negative effect was maintained over time.

Additionally, based on data provided by the 46 participants, responses for the target words asa 'handle' and sacudidor 'feather duster' were given 44 times on Post-test 1 and 39 times on Post-test 2. Of these 83 responses, none included an incorrect inversion of the target words back to the order in which the words had appeared in the learning phase, suggesting that these results reflect vocabulary learning beyond learning of a single presentation order.

IV Discussion

The findings of both experiments indicate that copying target words negatively affected productive L2 vocabulary learning. This section discusses the implications of these findings with regard to research on sentence writing and vocabulary, the resource depletion for output hypothesis, and the effects of word writing in different types of experimental paradigms.

Previous studies on sentence writing and L2 vocabulary learning found that requiring learners to write new words in sentences had strong negative effects on productive word gain. Barcroft (1998;2000;2004) found decreases in the area of 100% for sentence writing as compared to no sentence writing. In the present study, word-writing scores were approximately 0.34 times lower (Experiment 1) and 0.21 times lower (Experiment 2) than no-writing scores. These numbers suggest that some, but not all, of the negative effect of sentence writing may be attributed to the act of copying target words. Semantic evaluation and other subtasks in sentence writing remain as other probable contributors to the large negative effect of sentence writing. The present findings are consistent with the resource depletion for output (RDO) hypothesis because they suggest that forcing learners to produce output without access can detract from learning new L2 words. If one considers the role of processing resource allocation in vocabulary learning, the predictions of RDO and the findings of the present study are not counter-intuitive. In order to learn a new word, one must allocate sufficient processing resources toward encoding the target word form, isolating an appropriate semantic representation, and mapping word form onto the semantic representation. In a sufficiently demanding vocabulary learning task, forced output without access can exhaust processing resources that could otherwise be directed toward encoding the word forms and developing form-meaning mappings. The RDO hypothesis and the present findings are also consistent with theoretical accounts that emphasize specificity of processing type, such as transfer-appropriate processing (Morris et al., 1977) and the type of processing -resource allocation model (Barcroft, 2000;2002) for lexical acquisition. From these perspectives, the sub-tasks involved word writing (e.g. motor activity, looking away from words on the screen) did not invoke the correct component processes needed for most effective vocabulary learning.

The combined findings of Thomas and Dieter (1987) and the present study also suggest that the effects of word writing may depend upon experimental paradigm and methodology. Whereas Thomas and Dieter found positive effects for word writing on some measures and null effects on others, the present study revealed negative effects for word writing using LPSP-written scoring. How can the difference in results between the two studies be explained?

Three potentially critical differences between the present study and Thomas and Dieter's (1987) study concern task difficulty, presentation format, and scoring. First, more target words were used in Thomas and Dieter's study, but the inclusion of an additional repetition for each word and an additional 4 seconds for every repetition may have resulted in a less demanding vocabulary learning task than that of the present study. If so, the negative effect of word writing via processing resource depletion may have been less detectable. Second, Thomas and Dieter presented target words both visually and orally. As such, word writing may have enabled participants to attend to sound-to-spelling correspondences in a manner that was more beneficial to encoding the new forms. Third, Thomas and Dieter's scoring method most sensitive to partial word form knowledge (most inclusion of partial word fragments) did not yield positive effects. In the present study, negative effects were obtained using LPSP-written scoring, which is very sensitive to partial word knowledge. Therefore, the potentially negative effects of word writing may be more detectable with measures that are more sensitive to partial word form knowledge.

V Future research

Additional research may help to explain the combined findings of Thomas and Dieter and the present study by manipulating factors such as the difficulty of the vocabulary learning task and the nature of the word-writing task. Future studies also may explore how alternative types of output affect vocabulary learning and other aspects of language learning. The present study demonstrated that forced output in the form of word writing detracted from L2 vocabulary learning in the context of a relatively demanding vocabulary learning task. From the perspective of processing resource allocation, forced output of this nature did not activate component processes needed for effective vocabulary learning but, instead, exhausted processing resources needed to encode new word forms and make form-meaning mappings. What other types of output might affect L2 vocabulary learning in this manner? Do these types of output affect other areas of L2 learning such as phonology and grammar in the same manner? Future research on these questions should help to advance our understanding of the impact of different types of output on L2 acquisition.

VI References

Barcroft, J. 1998: L2 vocabulary learning: do sentence writing and oral repetition help? Poster Presentation at the Second Language Research Forum, Honolulu, HI.

Table 1

 1 Experiment 1: means for condition over time

	Time	Condition*	Mean	SD
	Immediate	No writing	5.75	2.16
		Word writing	4.30	2.54
	2 days later	No writing	4.16	2.80
		Word writing	3.13	2.78
	Overall	No writing	4.95	2.41
		Word writing	3.71	2.61

Note: *n ϭ 16 for each condition.

Table 2

 2 Experiment 2: means for condition over time

	Time	Condition*	Mean	SD
	Immediate	No writing	6.50	2.30
		Word writing	5.48	2.35
	2 days later	No writing	5.04	2.39
		Word writing	4.05	2.29
	Overall	No writing	5.77	2.29
		Word writing	4.77	2.22
	Note: *n ϭ 46 for each condition.


Lecturer, Rebecca Adams
email: rebecca.adams@vuw.ac.nz

Linguistics in your inbox: a review of listservs for second language research

The purpose of this review is to give a comparative overview of current listservs for applied linguistics researchers, with particular focus on their relevance to research on second language acquisition and use. Six listservs, based in different locations and targeted at different general audiences were selected and monitored for a sixmonth period. This review describes each, with particular attention to the volume of messages, the level of interaction among list users, the topics commonly discussed and the quality of information in each. This review is intended to serve both as a comparison of different listservs and as an introduction to the use of listservs for researchers and students who may not currently use them. It is not intended to present an exhaustive list of the many local and international listservs.

I Introduction

Traditionally, second language research has been conducted in locations spread throughout the world. While North America and Western Europe have long been centers of second language research, wellestablished research and educational institutions with a focus on second language research have flourished worldwide. There are benefits, therefore, of electronic communication both for strengthening local research communities and for bringing the wider second language community closer together, allowing for the exchange of information in the field and discussion of current and on-going second language research. This has happened through the proliferation of university, organizational, and personal webpages dedicated to second language research (for a very extensive review of these see Gottwald, 2002), as well as through the use of listservs that allow researchers from around the world to communicate on matters relating to second language research.

Listservs are email lists that allow groups of users to communicate with each other via group emails. Often sponsored by an institution or organization, listservs are maintained by an owner who monitors and manages the communication, ensuring that inappropriate content (such as commercial solicitations or email viruses) are not passed through the listserv. Many listservs are maintained within academic institutions for communication among faculty or students; others are public listservs intended to provide an opportunity for communication throughout the research community. Most listservs are free, and can be subscribed to by sending an email to the listserv Webmaster.

While linguistics listservs can be a valuable tool for researchers in North America and Europe, they can also be particularly important for researchers working in smaller research communities, both to build local communities and to give access to communication with other researchers in the field. The purpose of this review article is to examine selected listservs that focus on second language research, considering which may be most relevant to second language researchers, and which promote an active exchange of ideas in second language research.

II Selection criteria

The listservs selected for this review met several criteria. One of the interesting features of listservs is that they allow for interaction among researchers. Thus, weblists, which are organizational lists used to mail information to users, were not included. For example, the Center for Applied Linguistics (CAL), a Washington DC-based non-profit research center that focuses on issues related to language learning and teaching, and the Center for Advanced Research on Language Acquisition (CARLA), a University of Minnesota-based research organization, each maintain influential weblists. However, the focus in the current review is on the use of electronic communication by individual researchers, rather than organizations, and for interaction, rather than solely for the dissemination of information. Second, the listservs included in this study all have a primary focus on second language research, rather than second language teaching. This excluded very active listservs such as TESL-L that primarily function as a means for teachers to elicit and exchange ideas and lesson plans. For similar reasons, primarily technical weblists like LLTI (Language Learning and Technology Information) were not included. While highly valuable, such listservs are less relevant to many second language researchers, and are not considered here.1 It should be noted that many listservs include information useful to both teachers and researchers, and that the distinction between pedagogical and research listservs should most likely be viewed as a continuum, rather than a binary distinction. While the listservs included in the current review differ in the exclusiveness of the focus on research, only listservs with a primary focus on research are considered here.

Additionally, listservs conducted in languages other than English were not considered in this review, as many may not be accessible to the readers of Second Language Research. Finally, listservs that are primarily directed at the applied linguistics community were preferred to those directed at a more general audience. However, the LINGUISTList was included, because, as the largest linguistics listserv, a large volume of applied linguistics information is communicated on the list. Following these criteria, six listservs were selected for review. These were American Association of Applied Linguists List (Aaal-l), Australian Linguistics List (Australian-linguistics-l), English as an Additional Language-Bilingual List (EAL-bilingual-l), Language Use List (Languse-l), Linguist List (LINGUISTList), and Language Testing List (LTEST-l). It should be noted that other listservs that fit these criteria were not included in the current review; rather, attempts were made to gather information on a representative sample of the available lists. Each list was monitored for a period of six months, between October 2004 and April 2005.

III Description of listservs

During this period, the listservs were monitored both for the topics included in discussions and for the purposes of the postings. Topics were defined through reading the emails received from listserv users, and topics were added throughout the monitoring period. Topics found in the emails sent to the listservs are summarized in Table 1. While Research in a particular language, including formal aspects, language use, and learning Sociolinguistics Issues related to language variation and social contexts of language use Computational linguistics Natural language processing, machine translation, and all other computational applications Theoretical linguistics Formal linguistics (including phonology, syntax, semantics, morphology, etc.) from a variety of perspectives General linguistics Other linguistic topics, including language typology, anthropological linguistics, and endangered languages many of these categories are overlapping or related, for the sake of simplicity each email contribution was categorized to only one topic, based on the most salient topic of discussion. Email contributions were categorized to help form a picture of the scope and focus of each listserv. The emails were also categorized according to the purpose of the contribution, to help characterize the functions the listserv plays in building the research community. Some email contributions provide information about events or resources, others are requests for help or responses to previous postings. The contributions to the listservs reviewed here functioned as described in Table 2. Contributions to the listservs were categorized according to function to give an idea of the types of discourse found in the listservs, as well as the level of interactive discussion, as opposed to general announcements, in each listserv. Again, some emails had multiple purposes, but all were categorized in one category only, according to the primary purpose of the contribution. Each contribution to each listserv from the six-month monitoring period was categorized according to topic and purpose. This information is summarized in Tables 3 and4 to allow for contrast of the six listservs reviewed here. Both the number of contributions in each topic and the percentage of the total contributions for each listserv are included. Contributions dealing with non-linguistic topics (e.g. jokes, virus warnings, hoax debunkings) are not included here. As can be seen, the lists differ substantially in common topics of discussion, ranging from a primary focus on theoretical linguistics topics (LINGUISTList) to primarily teaching and classroom second language acqussition (SLA) topics (EAL-bilingual-l). It is also clear that some lists are much more active than others, a point born out in Table 4, which displays the purpose of contributions to the listservs. Note: *All contributions to LTest-l were primarily focused on language assessment, so it was not meaningful to categorize them in this way. Topics indicated here are secondary topics addressed in these contributions.

For all the listservs except EAL-bilingual-l and LTEST-l, the most common types of contributions are informational in purpose, giving information on conferences and institutes, new publications, and jobs openings in linguistics. EAL-bilingual-l, LTEST-l, and Languse-l differ from the remaining listservs in having a large proportion of postings as responses to previous contributions. These listservs overall were much more interactive, and in each one extended discussion was created and maintained on topics of interest. These differences are discussed below, as each listserv is discussed in turn.

American Association of Applied Linguistics List (Aaal-l)

The Aaal-l is sponsored by the American Association of Applied Linguistics, and is intended to connect applied linguists across North America. Users can receive the emails individually, or in a daily digest, which summarizes the messages for each day. Extensive archives are available for this list, dating back to July 1997. The archives contain the full listserv content, and are not searchable, but are browsable by subject, author, and date or in a full-month digest. The list is relatively quiet; during the six months of monitoring, only 76 messages were sent among members of the list. There were postings from both Europe and North America to the list; however, the vast majority of messages sent to the list were from North America. While relatively few messages were sent, the almost all of those sent were relevant to applied linguists, and covered a variety of research areas, including generative approaches, cognitive linguistics, and second language discourse. Messages relating to second language teaching, language teacher education, socio-linguistics, and the acquisition of various languages were also frequent.

Many of these messages were informational in nature; more than 40% of the messages were calls for participation in conferences or research institutes. Other common informational purposes included job listings and announcements of new publications. A much smaller proportion of the messages called for responses. It should be noted that there was no response on the list for most of these messages. For example, requests for information on specific topics in applied linguistics research, including language testing, interpretation, and language pedagogy evoked no responses to the general list. While it is likely that some responses were sent to individuals rather than the entire list, this did limit the amount of discussion on the list. Occasionally, responses were posted to the list. For example, one list-user asked for leads on research on the acquisition of tense and aspect of L1 Mandarin or Cantonese learners of English. The second posting of this request elicited one response suggesting a study that might be of interest. In no instance were multiple responses from different users posted to the list. The list is a good source of information on events in applied linguistics, and the relatively low volume of messages makes the information very manageable. For spreading information on conferences, publications, and jobs this listserv is a very helpful resource for second language researchers. However, for generating discussion in the field or for seeking input on research, it does not seem to be as useful.

Australian Linguistics List (Australian-linguistics-l)

The Australian-linguistics-l is an Australian-based list which was launched to provide a means of communication among linguists in Australia. The list is affiliated with the Australian Linguistics Society and is owned by the Australian National University. The archives for this list, while not searchable, can be browsed by month, with monthly fulltext archives dating back to April 1997. Although the list is not specific to second language research, all posting to the list during the six months it was monitored were relevant to applied linguistics.2 This list is additionally of interest because it was not based in the relatively more populated North American and European linguistics communities. If one of the purposes of listservs is to increase communication among linguists over geographic areas, lists based in more isolated areas may be particularly important for second language researchers. As mentioned in the introduction to this review, one of the purposes of this review was to evaluate the benefits of local listservs in specific research communities.

The Australian-linguistics-l is the least active of the listservs reviewed here, with only 19 messages in the six-month period. The bulk of the messages dealt with issues relating to bilingualism and biculturalism, particularly with respect to indigenous language minority groups in Australia and Austral-Asia. The majority of postings to the list came from Australia, with very few contributions from New Zealand and other Pacific nations. The messages to the list were quite evenly split among messages alerting members to media items of interest, information on publications, and information on academic job postings. While many of the postings were informational, there were several requests for assistance with finding academic literature and for others' input on research projects. During the monitoring period, only one message mailed to the list contained a response to a previous request, in this case a request for leads on corpora for native Australian languages. Again, it is possible that responses to more issues were sent to individuals, rather than to the entire list, but this leaves little opportunity for group discussion. While not very interactive in nature, this list would be very useful to anyone interested in issues particular to applied linguistics in Australia. The list differs from others in this review in the narrowness of the focus. Most listservs include a much wider range of topics. While such listservs clearly are helpful for a wider audience, the narrow focus here (and to a lesser degree in the LTEST-l) may be more effective for spreading information to a targeted community without the overwhelming volume of messages disseminated in more expansive listservs.

3 English as an Additional Language-Bilingual List (EAL-bilingual-l) EAL-bilingual-l is dedicated to research and practice in the acquisition of English as a second language and bilingualism. Based in the United Kingdom, its purpose is to allow researchers and teachers to discuss issues related to language learning and teaching, particularly among language minority communities. EAL-bilingual-l was moderately active, with 143 messages during the six months the list was monitored. The contributors to the site were almost entirely British, and the majority of the topics covered were relevant to second language learners and second language users in British schools. Close to a third of the communication dealt with language learning and teaching in British schools. Another third dealt with issues relating to bilingual and multilingual minority communities in the UK. This list was also the most active of those included in this review in the discussion of computer-assisted language learning (CALL) and language teacher education (LTE). Of the second language research listservs reviewed here, this list had the most substantial proportion of second language teaching information.

The nature of the communication on this list is strikingly different to those reviewed previously. Close to 60% of the messages sent to listserv users were responses to previous postings. Overall, there was a high level of interaction on this listserv. Requests for information and insights to research were rarely disregarded, and several prompted extended exchanges among list users. For example, an extended multi-day discussion was prompted by one contributor questioning the use of the coined word 'languaging' by a speaker at a recent conference. Five different list users commented on this, exchanging views on their interpretation of the speaker's intended meaning, other ways that this meaning had previously been discussed, and the importance of the idea it represented for second language learning. Similarly, a message expressing concern that a language education policy document was not posted on a central website lead first to an explanation of where to find the document, and then a further multi-email exchange from other users explaining where further information on the policy could be found. Quite a substantial portion of the postings on the list dealt with the treatment of language learning and language minority groups in the media, and such postings often sparked reactions among the listserv members. For instance, an email seeking web-based resources for teaching about tolerance and diversity in multicultural educational settings received seven responses suggesting websites and materials. Incidentally, this list is the only one reviewed here that is used to spread information about specific educational policies and curricular resources. While the list is primarily of interest to those involved in second language teaching in the UK, much of the information would be useful to language researchers with interests in language minority communities and bilingual education. While the contributions to the listserv primarily relate to the UK context, the density of information on multilingual communities in the UK provides a level of detail that would allow for comparison to other contexts.

Language Use List (Languse-l)

The Languse-l list is sponsored by Temple University and is available in both regular (individual messages) or digest form. Its focus is on the study of discourse (both first and second language), with additional focus on the social contexts of second language learning and use. Archives for this listserv, dating back to May 1999, can be browsed by date, subject, author, or thread. With only 54 postings over a six-month period, Languse-l was not a particularly active listserv. However, the contributions to this list come from all over the world; the 54 postings included in this review included emails from researchers located throughout North and South America, as well as Asian nations including Thailand and China, Australia, and several European nations. Despite the relatively low level of activity on Languse-l, it was one of the most international lists surveyed here. Most of the postings dealt with discourse analysis, either of first or second language use, or the social contexts of language use. While both first and second language use were featured, first language data featured more prominently than second language data. However, many of the discussions would be relevant to second language researchers as well.

The messages sent to the listserv served mainly to announce conferences, seek input on research, and respond to research. This listserv had the highest proportion of requests for input on research. For the most part, these took the form of contributors sharing some data or describing a phenomenon and asking for help with the analysis, suggestions of underlying causes, or insights from other research contexts to help explain the data. For example, in one exchange that involved multiple emails by two researchers, the analysis of gesture as part of communication was discussed. The original email began as a request for help in finding sources that criticized conversation analysis for not dealing adequately with the role of gesture; in further emails, what might actually constitute 'adequate treatment' of gesture was questioned and developed. While starting with a simple request for finding sources, this interchange allowed for a useful refinement of the constructs involved. Most requests received only one response; however, very few requests did not receive responses. The level of interaction among list members was not as high as on EALbilingual-l, but the listserv did still seem to provide a forum where researchers gave input into each other's research. The listserv does not provide an overwhelming number of emails, but the information posted is generally quite useful and the discussions very insightful. In one instance, a researcher asked for suggestions on the origin and use of a particular discourse item in which a change in the phonological form is used to intensify the meaning. In the ensuing discussion, list users mentioned similar uses of phonological modifications and suggested possible origins of the usage. In a summary of the information he received, the researcher who began the discussion gave credit to list users for giving him suggestions that lead him to further data, allowing him to more fully analyse the usage. In this case, the interactive nature of the list was particularly helpful in increasing understanding of the research topic. While much of the information on this list is not specific to second language research, it is a valuable resource for anyone interested in second language use and the connections between second language use and society.

The Linguist List (LINGUISTList)

LINGUISTList is sponsored by the Linguistic Society of America and is co-managed by linguists from Wayne State University and Eastern Michigan University. While not a specific second language research site, the LINGUISTList is by far the most active listserv in linguistics, and provides a greater amount of information on second language research than any of the other listservs reviewed here. The listserv is available in either a regular or digest form; because of the large volume of messages (over 1600 in the six-month period reviewed here) the digest form is strongly recommended. Full-text archives dating back to December 1990 are also available. The non-searchable archives are grouped by week from June 1991 on; prior to that they were grouped by month. The LINGUISTList provides a meeting ground for linguists across disciplines and across geographic areas. There is active participation from linguists in North America and Western Europe, with significant participation from linguists in Asia and Latin America.

While postings on all topics related to linguistics are encouraged, the majority of the information deals with theoretical topics such as syntax, semantics, and phonology and sociolinguistic topics, particularly linguistic variation. This is the only listserv with a sizable contribution from computational linguists; while little of this is directed at second language research, linguists interested in computational models of language learning would find much of use here. The LINGUISTList also includes the largest proportion of information on translation. There is an almost equal incidence of messages related to second language learning and teaching as to other applied linguistics topics. Non-SLA applied linguistics topics are mainly focused on psycholinguistics, cognitive linguistics, and language policy. While many of these contributions are not specifically on second language learning and use, many would still be relevant to second language researchers. Contributions on second language acquisition and teaching were relatively infrequent in the list. The majority of these were announcements of job openings in academic and research institutions.

Like the other lists, the messages were designed to inform readers about events and opportunities, to announce new publications, and to support research. However, the purposes of postings were much more varied here than on the other listservs in this review. While a similar proportion of messages announcing conferences and issuing calls for proposals were found on LINGUISTList and other lists reviewed here, LINGUISTList is unique in the volume of informational messages about institutes and summer seminars in linguistic topics advertised through the listserv. This list also had an unusually high volume of informational messages that announced job openings for second language researchers and teachers. The LINGUISTList is an invaluable resource for anyone seeking employment in fields relevant to second language studies. Other informational emails on this list included frequent announcements about grant funding opportunities. Informational postings comprised more than half of the 71 SLArelated posts examined for this review.

There was a relatively higher proportion of emails were directed at advertising new publications on LINGUISTList compared to other listservs reviewed here. There were frequent postings to announce the publication of new books as well as to publicize the tables of contents of current journal issues from a range of topics in linguistics, including many publications relevant to second language studies. The listserv is also used as a means of announcing the publication of new dissertation research, much of which is of interest to second language researchers. Additionally, this was the only listserv to sponsor book reviews of new publications in linguistics. During the six months that the listserv was monitored for this review, reviews of applied linguistics publications were frequent. Messages that promoted new publications in any of these manners made up slightly less than half of the SLA postings during the period this list was monitored.

The third major purpose of LINGUISTList messages was fostering communication among researchers. While a relatively small proportion of the business on this listserv involves interaction among linguists, the LINGUISTList fosters discourse on linguistics in several ways. Users can post questions to the list (often seeking references or input on the analysis of linguistic data) or can pose more general questions to start a discussion. Responses can be sent to individuals or to the list as a whole, but users are encouraged to post summaries of the responses they received to their questions, so the whole list benefits from the ideas exchanged. These resources are largely untapped by applied linguists. While the listserv was monitored for this review, no second language data questions or summaries were posted, and only one discussion topic relevant to applied linguistics was posed. No responses to this topic were sent to the list, although they may have been sent to the individual list user who posted the topic. Because it is not directed at second language researchers, the LINGUISTList may not be the best forum for exchanging ideas among the second language research community; however, it is a helpful resource for keeping abreast of conferences and publications in applied linguistics. Greater use of the listserv to discuss research and theories in second language acquisition could increase its utility for fostering discussion among second language researchers worldwide.

Language testing list (LTEST-l)

The Language Testing list is sponsored by Penn State University. It functions as a meeting point for linguists and teachers interested in second language testing research and practice. LTEST-l is one of the busier listservs included here: there were 187 messages sent in the time that the list was monitored (not including a rather large volume of emails addressing problems on the list with viruses and virus hoaxes). It was also one of the most international, with contributions from researchers in North America, Europe, and the Pacific quite common. While virtually all of the emails sent to the list focused specifically on language testing, there were also a number of messages focused on language teaching, and particularly the relationship between language teaching practice and language testing. In terms of topics overall, however, this was the most homogenous list included here.

The narrow definition of scope on this list seemed to have two effects. First, there were few emails that were irrelevant to the majority of the listserv users and, second, there was a very high degree of interaction and sense of community among the list users. Indeed, this was the only listserv with a very international audience to have a high proportion of messages sent as responses to others' requests for help in locating research literature and resources as well as to solicitations for input to research projects. Multiple messages sent from different researchers in response to a question or request were not uncommon on this list, giving the sense of a close, approachable internet community. In one instance, a list user posted a message seeking information on second language proficiency tests in Spanish. Over the following few days, 10 responses were received. The first two responses supplied names and information on the tests and, following this, the thread evolved into a discussion of the procedures involved in validating one of those tests, including questions about the peer review process and the implementation effect of reporting test validation in English rather than Spanish. While list users presented opposing arguments and viewpoints, they carefully did so in a respectful manner that encouraged further discussion. There was a similar sense of community in the announcements for conferences. Beyond the initial calls for conference papers there were several messages including information about social events at conferences and reminders of conference fee deadlines. LTEST-l was unique in the listservs reviewed here in terms of the type of discourse generated. Finally, the list was also commonly used to advertise conferences and publications on second language testing as well as to inform users of job opportunities in language testing.

IV Conclusions

All of the listservs reviewed here fill an important role in the dissemination of information in second language research, particularly with respect to publicizing conferences and new publications. The relevance of this information to individual researchers depends of course on research interests. Hopefully, this review has introduced readers to some new resources and given them information to help determine which is more relevant to them.

In terms of stimulating and fostering discussion among second language researchers, smaller, more focused listservs may provide a better forum for extended dialogue and debate. Such listservs may also better serve as a resource for soliciting and receiving help in research projects. Both listservs that are focused in terms of geographic area and those that are focused in terms of topic area are more likely to foster an exchange of ideas. While subscribing to larger listservs like the LINGUISTList may be the most efficient means of gaining information on events and publications, smaller, more narrowly focuses listservs may be a better medium for engaging in discussion.

V Reference

Gottwald, S. 2002: Websites for second language research. Second Language Research 18, 83-94.

Table 1

 1 Topics of contributions

	Topic	Description
	Second language acquisition (SLA)	Research on second language learning
		processes
	Second language pedagogy (SLP)	Language teaching and classroom
		language learning
	Computer assisted language	Language teaching and learning
	learning (CALL)	technology
	Corpus linguistics	Use of corpus for research and teaching in
		theoretical or applied linguistics
	Language assessment	Issues in the design of use of assessment
	Language teacher education (LTE)	Research and practice in teacher education
	Bilingualism	Bilingualism and multilingualism, bilingual
		education
	Translation	Translation and interpretation, translator
		qualification
	Applied linguistics	Any applied linguistic topic not intrinsically
		related to second language learning or
		use, including first language acquisition,
		psycholinguistics, and neurolinguistics
	Language studies

Table 2

 2 Purpose of contributions

	Purpose	Description
	Conferences/institutes	Providing information (and calls for proposals)
		for conferences and special topic institutes
	Conference information	Providing further details (e.g. location, dates,
		reminders about registration) for conference
		participants
	Publications	Information about new publications (print and
		electronic; books and journals) and calls for
		submissions to publications
	Reviews	Reviews of recent publications
	Grants/fellowships	Information for applicants for external grants
		and postgraduate support
	Postgraduate	Information on (new) postgraduate programs
		in linguistics
	Jobs	Listings of academic and other jobs,
		post-doctoral positions
	Media	Drawing attention to news reports citing
		linguistic research
	Activism	Information on social issues of concern to
		linguistic minority communities
	Linguist finder	Seeking contact information for other
		researchers
	References	Seeking previous research literature on a
		research topic
	Resources	Seeking information on resources for
		linguistics research
	Seeking input	Seeking others' input on research plans and
		data analysis
	Responses	Responses to previous requests or comments
	Recognition	Announce awards and achievements of
		prominent linguists, obituary notices
	Schools/curriculum	Information on educational policies relevant to
		second language research

Table 3

 3 Topics of listserv contributions: number of contributions in each topic (percentage of total contribution for each listserv in brackets)

	Topics	Aaal-l	Australian-EAL-		LINGUIST-
			linguistics-l bilingual-l Languse-l List	LTEST-l
	SLA	9 (12%) 1 (5%)	2 (1%)	1 (2%)	71 (4%)	2 (1%)
	SLP	11 (14%)		49 (34%)	2 (4%)	73 (5%)	24 (13%)
	CALL	1 (1%)		15 (10%)	1 (2%)	7 (0.4%)	2 (1%)
	Corpus					55 (3%)	6 (3%)
	linguistics
	Language	3 (4%)		8 (6%)		3 (0.2%)	*
	assessment
	LTE	8 (11%)		16 (11%)		5 (0.3%)	1 (0.5%)
	Bilingualism	4 (5%) 14 (74%)	49 (34%)		26 (2%)	1 (0.5%)
	Translation					42 (3%)
	Applied	12 (16%) 2 (10%)	1 (1%)	17 (32%) 129 (8%)	1 (0.5%)
	linguistics
	Language	9 (12%)				135 (8%)	22 (12%)
	studies
	Socio-linguistics 7 (9%)	1 (5%)		30 (56%) 200 (12%)
	Computational					140 (9%)
	linguistics
	Theoretical	3 (4%)				585 (36%)
	linguistics
	General	1 (1%)			3 (6%)	135 (8%)
	linguistics

Table 4

 4 Purpose of listserv contributions: number of contributions in each topic (percentage of total contribution for each listserv in brackets)

	Purpose	Aaal-l	Australian-EAL-		LINGUIST-
			linguistics-l bilingual-l Languse-l List	LTEST-l
	Conferences/ 33 (43%) 2 (11%)	12 (8%)	17 (31%) 504 (31%)	13 (7%)
	Institutes
	Conference	1 (1%)				1 (Ͻ 0.1%) 11 (6%)
	Information
	Publications	9 (12%) 3 (16%)	2 (1%)	4 (7%)	430 (27%)	7 (4%)
	Reviews					89 (6%)
	Grants/	3 (4%)				29 (2%)	2 (1%)
	fellowships
	Postgraduate	1 (1%)		4 (3%)		8 (1%)	1 (0.5%)
	Jobs	6 (8%) 3 (16%)	4 (3%)	1 (2%)	248 (15%)	19 (10%)
	Media		4 (21%)	9 (6%)		35 (2%)
	Activism	1 (1%)		2 (1%)		2 (Ͼ0.1%)
	Linguist finder 4 (5%)		2 (1%)		3 (Ͼ0.1%)	3 (2%)
	References	5 (7%) 2 (11%)	1 (1%)	1 (2%)	58 (4%)	7 (4%)
	Resources					47 (3%)	6 (3%)
	Seeking input 3 (4%) 3 (16%)	9 (6%)	13 (24%)	80 (5%)	12 (6%)
	Responses	4 (5%) 1 (5%)	84 (59%) 17 (31%)	59 (4%)	102 (55%)
	Recognition	1 (1%) 1 (5%)			9 (1%)	1 (1%)
	Schools/			13 (9%)
	curriculum

LLTI, while clearly of value to second language researchers, primarily deals with discussion of computer systems and software. After monitoring the list for four weeks and finding only one message discussing the use of technology in second language learning (as opposed to the technical requirements of programs or software recommendations to teachers), it was decided to exclude the listserv.

The Applied Linguistics Association of Australia (ALAA) has since the beginning of writing this article re-organized their listserv (APPLIX), which had previously been defunct for a number of years.


Frederik L Giesel

Max Schoebinger

Waldemar Hosch

Hendrik Von Tengg-Kobligk

Hans-Peter Meinzer

Jens-Rainer Allenberg

Hans-Ulrich Kauczor

Dittmar Böckler

Editor in Chief, Mark A Creager

Images in vascular medicine

à la diffusion de documents scientifiques de niveau recherche, publiés ou non, émanant des établissements d'enseignement et de recherche français ou étrangers, des laboratoires publics ou privés.

imaging with multidetector computed tomography (MD-CT) revealed a 5.0 ϫ 4.0 ϫ 2.7 cm tumor of soft tissue density, heterogeneous contrast medium enhancement derivation from the infrarenal vena cava and infiltrating the surrounding tissue. Panel A shows contrast-enhanced CT in the axial (a) and coronal (b) reconstructed view demonstrating an abdominal mass (arrow). A primary leiomyosarcoma of the vena cava inferior was assumed. Staging using CT thorax and bone scintigraphy presented no evidence of metastatic spread. Phlebography of the vena cava inferior confirmed an obstruction of lumen (Panel B, arrow) with prominent lumbar veins for collateral venous blood flow via azygos and hemiazygos veins. For surgical planning, multiphasic magnetic resonance angiography (CE-MRA) (Panel C, arrow) was performed to evaluate the degree of vascular involvement (local tumor infiltration and renal vessel involvement), but tumor involvement of renal venous vasculature was still uncertain.

Therefore, computer-assisted surgical planning using the three-dimensional (3D) surface rendering technique was performed based on multiphasic CE-MRA raw data

Images in vascular medicine

Vena cava leiomyosarcoma: preoperative planning with complex vessel reconstruction using 3D surface rendering algorithms After resection of the leiomyosarcoma, the vena cava was reconstructed by a prosthetic tube graft. The operation confirmed pre-surgical imaging results (Panel D). Pathological examination revealed a middle-differentiated, spindled sarcoma (G2). The postoperative course was uneventful, and the patient was discharged two weeks after adjuvant radiotherapy. At one-year followup, the patient presented healthy with a patent graft and without recurrence of malignancy.

Leiomyosarcoma is a rare malignancy of smooth muscle. More than half are located in retroperitoneal or intra-abdominal sites presenting a major clinical challenge. Most tumors are large, making it difficult to obtain adequate margins of resection. The prognosis depends on the histopathological grade, tumor size, and evidence of metastasis. [START_REF] Lewin | Tumors of the esophagus and stomach. Atlas of tumor pathology[END_REF] The 5-year survival for patients with low-grade tumors is more than 90% versus 50% for high-grade tumors. Sarcoma of the inferior vena cava is a rare clinical entity that has been reported in fewer than 300 patients. [START_REF] Mingoli | International registry of inferior vena cava leiomyosarcoma: analysis and search of world literature on 141 patients and report of three new cases[END_REF] Vascular involvement is also a basis for unresectability of other retroperitoneal soft tissue sarcomas. Therefore, detailed and exact preoperative imaging is necessary and may influence late survival of these patients. Magnetic resonance imaging (MRI) and CT display the anatomic and structural details of the tumor, adjacent structures and morphological relationship to confluent veins with high accuracy. In addition to this information, 3D surface rendering and 'fly-through' are of increasing interest for vascular surgeons, being a tool of preoperative surgical navigation. [START_REF] Robb | Patient-specific anatomic models from three dimensional medical image data for clinical applications in surgery and endoscopy[END_REF] The 'fly-through' option is a promising navigation tool within the frame of interventional medicine. This initial experience indicates that 3D surface rendering is an additional non-invasive and helpful procedure that allows clear visualization by providing detailed 3D depiction of the vascular involvement of arteries and/or veins in malignancy.

However, manual data segmentation is still timeconsuming and requires the interdisciplinary approach of radiologists, vascular surgeons and computer scientists. Further studies and improved software skills will be needed to assess the definitive efficacy of this modality in the preoperative assessment of vascular tumors prior to resection.

Movie 1 General overview provided as a rotation around the longitudinal axis of the body. Semi-automatic segmentation tools allowed the accurate delineation of the vena cava (blue), as well as the aorta (red), the liver (grey), the kidneys (brown) and the gall bladder (green). Virtual cuts give an insight into the vena cava, the cava sarcoma (white) and its involvement.

Movie 2 Virtual fly-through of the vena cava. First, the scene is tipped over to provide a cranio-caudal view. Then, the virtual camera is propagated along a flight path defined interactively by the user. The camera is guided to the renal veins, which were marked red for a better depiction. Then, the tumor is passed at the widest point of constriction and the flight ends in the common iliac veins.

  (Panel D). The virtual imaging techniques allowed an intra-luminal view and revealed left and right renal veins without direct tumor involvement (Panel D). Results of computer-assisted planning are as follows: vena cava (blue) and tumor (hatched) (Panel D, left) have been Vascular Medicine 2005; 10: 55-57 © 2005 Edward Arnold (Publishers) Ltd 10.1191/1358863x05vm577xx

FrederikL

  Giesel a , Max Schoebinger b , Waldemar Hosch c , Hendrik von Tengg-Kobligk a , Hans-Peter Meinzer b , Jens-Rainer Allenberg d , Hans-Ulrich Kauczor a and Dittmar Böckler d Departments of a Radiology and b Bioinformatics, German Cancer Research Center, Heidelberg, Germany; Departments of c Radiology and d Vascular Surgery, Heidelberg University Hospital, Germany Address for correspondence: Dittmar Böckler, Department of Vascular Surgery, University of Heidelberg, Im Neuenheimer Feld (INF) 110, 69120 Heidelberg, Germany. Tel: ϩ49 6221 566249; Fax: ϩ49 6221 565423; E-mail: dittmar_boeckler@med. uni-heidelberg.de Video footage of this can be seen at http://www. vascularmedjournal.com by clicking on the 'Additional material' button. year-old woman with diffuse abdominal pain and weight loss of 5 kg (total body weight 60 kg) in 2 months was referred to our institution with the diagnosis of a pancreatic mass based on an ultrasound scan performed at an outside institution. Initial cross-sectional clipped with a coronar plane to provide a view into the lumen; right: exemplary intraluminal views (Panel D, (a) cranio-caudal view; (b) cross-section; (c) caudo-cranial view) placed at different positions indicated by green lines. Arbitrary camera positioning and interactive measurement tools allowed the qualitative and quantitative assessment of tumor size and amount of stenosis. It was confirmed that the renal veins were not involved.


Two years have passed since we first gathered together researchers from around the world to exchange their thoughts and data. Since that meeting in Hamburg, Germany, the evidence has grown that ADMA plays a significant role in cardiovascular physiology and pathology. The rapid growth of the field compelled a second meeting, held in New Orleans in November 2004. This issue of Vascular Medicine contains the proceedings from that meeting, at which new and exciting data emerged, of scientific interest and clinical relevance.

ADMA is asymmetric dimethylarginine, an endogenous inhibitor of nitric oxide (NO) synthase. ADMA has been recognized as a metabolite since the 1970s, but its functional role as a competitive inhibitor of NO synthase was first described by one of us (PV) in 1992. [START_REF] Vallance | Accumulation of an endogenous inhibitor of NO synthesis in chronic renal failure[END_REF] Although the importance of this molecule was immediately apparent to endothelial biologists, ADMA did not attract the attention of the general scientific and clinical community until recently. Cardiologists, nephrologists, pharmacologists and others are currently among those who are actively pursuing research on ADMA. This is witnessed by the rapidly increasing number of scientific publications on the topic (the numeric results of a recent MEDLINE search are displayed in Figure 1). We anticipate a surge in interest from clinical investigators now that the scientific foundation has been laid, and now there are high throughput technologies for measurement of ADMA.

In October 2002, first attempts were made to understand the biosynthesis and metabolism of ADMA as well as some of its biological effects in the cardiovascular system. During our discussions at the first meeting in 2002 it became clear that an effort was needed to standardize analytical methods to measure ADMA because data generated by different groups of researchers and by different methods varied widely. At that time, the first studies had been published, which showed a relationship between ADMA and cardiovascular endpoints in controlled clinical trials. [START_REF] Miyazaki | Endogenous nitric oxide synthase inhibitor: a novel marker of atherosclerosis[END_REF][START_REF] Zoccali | Asymmetric dimethylarginine (ADMA): an endogenous inhibitor of nitric oxide synthase predicts mortality in end-stage renal disease (ESRD)[END_REF][START_REF] Valkonen | Risk of acute coronary events and serum concentration of asymmetrical dimethylarginine[END_REF] By November 2004, the role of ADMA as an emerging cardiovascular risk factor had been much more firmly established by multiple studies in different patient populations. The physiological importance of ADMA has been strongly supported by observations made using the DDAH transgenic mouse. [START_REF] Dayoub | Dimethylarginine dimethylaminohydrolase regulates nitric oxide synthesis: genetic and physiological evidence[END_REF] Early results from a DDAH knockout mouse appear to be consistent with the role of ADMA as a negative regulator of NO synthase. The mechanisms by which ADMA becomes elevated in patients with cardiovascular disease have been elucidated (for recent reviews see Böger 2003, [START_REF] Böger | The emerging role of ADMA as a novel cardiovascular risk factor[END_REF] Cooke 2004, [START_REF] Cooke | Asymmetrical dimethylarginine: the Über marker?[END_REF] enzyme inhibitors, angiotensin receptor antagonists, and insulin sensitizing agents (metformin and rosiglitazone). However, we are still lacking specific interventions to reduce plasma ADMA.

All of these new data, as they were presented during the Second International Symposium on ADMA -an Emerging Cardiovascular Risk Factor, are condensed into this supplemental issue to Vascular Medicine. This supplement provides a comprehensive overview on ADMA for researchers and clinicians alike who are interested in this emerging field of vascular biology and medicine.

Certainly, there are still open questions: What are the exact levels of ADMA in various tissues? Which isoform of DDAH contributes to its metabolism in various diseases? Is ADMA a widely applicable disease marker useful for primary prevention in patients with severe disease? Large prospective clinical trials will be needed to answer these questions; however, we feel that the stage is set to do so, and we anticipate that we will have more answers to these questions when we reconvene in London in 2006.

  Vallance and Leiper 2004 8 ). Several therapeutic agents have been shown to reduce plasma ADMA levels in patients and those with risk factors, including angiotensin converting Editorial ADMA: an emerging cardiovascular risk factor Rainer H Böger a , John P Cooke b and Patrick Vallance c (guest editors) a Clinical Pharmacology Unit, Institute of Experimental and Clinical Pharmacology and Toxicology, University Hospital Hamburg-Eppendorf, Germany; b Section of Vascular Medicine, Falk Cardiovascular Research Center, Stanford University School of Medicine, Stanford, CA, USA; c Centre for Clinical Pharmacology, The British Heart Foundation Laboratories, University College London, UK Address for correspondence: Rainer H Böger, Clinical Pharmacology Unit, Institute of Experimental and Clinical Pharmacology and Toxicology, University Hospital Hamburg-Eppendorf, Germany. E-mail: boeger@uke.uni-hamburg.de

Figure 1

 1 Figure 1 Numeric results of a MEDLINE search dated 19 January 2005, which included the search terms 'ADMA' and 'asymmetric dimethylarginine'.

© 2005 Edward Arnold (Publishers) Ltd 10.1191/1358863x05vm594ed


Shelagh Anthony

James Leiper
email: james.leiper@ucl.ac.uk

Patrick Vallance

Endogenous production of nitric oxide synthase inhibitors

Keywords: asymmetric methylarginine, dimethylarginine dimethylaminohydrolase, nitric oxide synthase, protein-arginine methyltransferase Vascular Medicine 2005, 10: S3-

Introduction

In 1986 Hibbs and colleagues identified N G monomethyl-L-arginine (L-NMMA) as a compound that inhibits cytotoxic effects of activated macrophages and prevents the release of nitrate and nitrite derived from L- arginine within these cells. [START_REF] Drapier | Murine cytotoxic activated macrophages inhibit aconitase in tumor cells. Inhibition involves the iron-sulfur prosthetic group and is reversible[END_REF] A year later, Furchgott's endothelium-derived relaxing factor was identified as nitric oxide (NO) [START_REF] Palmer | Nitric oxide release accounts for the biological activity of endothelium-derived relaxing factor[END_REF] and it soon became clear that L-arginine was the substrate for endothelial NO (eNO) generation in a process inhibited by L-NMMA. [START_REF] Palmer | Vascular endothelial cells synthesize nitric oxide from L-arginine[END_REF] Very soon L-NMMA became the standard pharmacological tool with which to probe the biological significance of the L-arginine:NO pathway in the cardiovascular, nervous and immune systems. Injection of L-NMMA was shown to increase blood pressure in guinea-pigs [START_REF] Aisaka | NG-methylarginine, an inhibitor of endothelium-derived nitric oxide synthesis, is a potent pressor agent in the guinea pig: does nitric oxide regulate blood pressure in vivo?[END_REF] and rabbits, [START_REF] Rees | Endogenous production of nitric oxide synthase inhibitors S7 Vascular Medicine 2005; 10: S3-9 Table 2 Conditions in which raised plasma concentrations of ADMA have been reported. Condition Species Reference Renal failure Human 41 Childhood hypertension Human 42 Pregnancy-induced Human 43 hypertension Pre-eclampsia Human 44 Experimental hypertension Rat 45 Pulmonary hypertension Human 46 associated with congenital heart disease Atherosclerosis Human 47 Rabbit 48 Hypercholesterolaemia Human 49 Rabbit 50 Thrombotic Human 51 microangiopathy Regenerated endothelial Rabbit 52 cells after angioplasty Heart failure Human 53 Rat 54 Cardiac syndrome X Human 55 Alloxan-induced Rabbit 56 hyperglycaemia Type 2 diabetes mellitus Human 57 Hyperhomocysteinaemia Monkey 58 Experimental Human 59 hyperhomocysteinaemia Stroke Human 60 Ischaemic proximal urethra Rabbit 61 Hyperthyroidism Human 62 Schizophrenia Human 63 Multiple sclerosis Human 64 Muscular dystrophy Human 65 Helicobacter pylori Human 66 infection of gastric mucosa[END_REF] and local intra-arterial infusion of the drug caused a dose-dependent arteriolar vasoconstriction in humans. [START_REF] Vallance | Effects of endotheliumderived nitric oxide on peripheral arteriolar tone in man[END_REF] It appeared that L-NMMA might even have therapeutic utility, and it has now been used to prevent the overproduction of NO that contributes to vasodilatation and hypotension in septic shock, [START_REF] Petros | Effects of a nitric oxide synthase inhibitor in humans with septic shock[END_REF] although it is not clear if this improves outcome. However, L-NMMA is also a naturally occurring arginine analogue. Together with asymmetric dimethylarginine (ADMA) and symmetric dimethylarginine (SDMA) it forms a trio of guanidine-substituted arginine analogues that have the potential to affect arginine handling and/or NO synthesis in biological systems (Figure 1). In this review we discuss the origin of these compounds, their biological effects and their possible clinical significance.

Identification of protein-arginine methyltransferase activity

The presence of methylated arginine residues within a range of proteins including myelin basic protein, [START_REF] Baldwin | Isolation and partial characterization of methylated arginines from the encephalitogenic basic protein of myelin[END_REF] heat shock proteins, [START_REF] Wang | Retinol influences contractile function and exerts an anti-proliferative effect on vascular smooth muscle cells through an endothelium-dependent mechanism[END_REF] and nuclear and nucleolar proteins [START_REF] Lischwe | Purification and partial characterisation of a nucleolar scleroderma antigen rich in NG,Ng-dimethylarginine[END_REF][START_REF] Lischwe | Clustering of glycine and Ng, NG-dimethylarginine in nucleolar protein C23[END_REF] has been known for many years. When initially identified in calf thymus, a single proteinarginine methyltransferase (PRMT) enzyme was thought to be responsible for the arginine methylation of all substrate proteins. [START_REF] Paik | Protein methylase I. Purification and properties of the enzyme[END_REF] However, advances in enzymology revealed two subtypes of PRMT activity (type I and type II) in mammals. One has a wide substrate specificity that includes histones and nonhistone nuclear proteins but has no activity toward myelin basic protein, and the second appears specifically to methylate myelin basic protein. [START_REF] Ghosh | Purification and molecular identification of two protein methylases I from calf brain. Myelin basic protein-and histone-specific enzyme[END_REF] Both types of PRMT utilise S-adenosyl methionine as a methyl donor and both produce S-adensoyl homocysteine as a by-product (Figure 2). More recent studies have indicated that, in the nucleus, the preferred substrates for the nonmyelin basic protein methyltransferase are RNA binding proteins (hnRNP) that constitute the nuclear RNA-splicing machinery. [START_REF] Najbauer | Peptides with sequences similar to glycine, arginine-rich motifs in proteins interacting with RNA are efficiently recognised by methyltrasferases modifying arginine in numerous proteins[END_REF] In addition to different substrate specificities, these two subclasses of PRMT appear to have different catalytic activities: the myelin basic protein-specific activity (type II) catalyses the formation of L-NMMA and SDMA, while the nonmyelin basic protein-specific activity (type I) catalyses the formation of L-NMMA and ADMA. [START_REF] Ghosh | Purification and molecular identification of two protein methylases I from calf brain. Myelin basic protein-and histone-specific enzyme[END_REF][START_REF] Rajpurohit | Enzymatic methylation of heterogenous nuclear ribonucleoprotein in isolated liver nuclei[END_REF] Thus type I PRMT activity is the major source of asymmetric methylarginines, and these are the ones that inhibit nitric oxide synthase (NOS).

Cloning of a gene family encoding human PRMTs

To date molecular cloning has revealed the presence of seven PRMT genes, PRMT1-7. [START_REF] Lin | The mammalian immediate-early TIS21 protein and the leukemiaassociated BTG1 protein interact with a protein-arginine N-methyltransferase[END_REF][START_REF] Katsanis | Identification and mapping of a novel human gene, HRMT1L1, homologous to the rat protein arginine N-methyltransferase 1 (PRMT1) gene[END_REF][START_REF] Tang | PRMT 3, a type I protein arginine N-methyltransferase that differs from PRMT1 in its oligomerization, subcellular localization, substrate specificity, and regulation[END_REF][START_REF] Chen | Regulation of transcription by a protein methyltransferase[END_REF][START_REF] Branscombe | PRMT5 (Janus kinase-binding protein 1) catalyzes the formation of symmetric dimethylarginine residues in proteins[END_REF][START_REF] Frankel | The novel human protein arginine N-methyltransferase PRMT6 is a nuclear enzyme displaying unique substrate specificity[END_REF][START_REF] Miranda | PRMT7 is a member of the protein arginine methyltransferase family with a distinct substrate specificity[END_REF] contain a conserved catalytic core region of about 310 amino acids, [START_REF] Tang | PRMT 3, a type I protein arginine N-methyltransferase that differs from PRMT1 in its oligomerization, subcellular localization, substrate specificity, and regulation[END_REF] however the sequence at the N-terminal of PRMTs is not well conserved.

Recombinant expression and enzymatic characterization of these genes has been used to classify the gene products as either type I or type II enzymes. This analysis has indicated that PRMT1-4 and 6 are type I and PRMT5 and 7 are type II enzymes. [START_REF] Lin | The mammalian immediate-early TIS21 protein and the leukemiaassociated BTG1 protein interact with a protein-arginine N-methyltransferase[END_REF][START_REF] Tang | PRMT 3, a type I protein arginine N-methyltransferase that differs from PRMT1 in its oligomerization, subcellular localization, substrate specificity, and regulation[END_REF][START_REF] Chen | Regulation of transcription by a protein methyltransferase[END_REF][START_REF] Branscombe | PRMT5 (Janus kinase-binding protein 1) catalyzes the formation of symmetric dimethylarginine residues in proteins[END_REF][START_REF] Frankel | The novel human protein arginine N-methyltransferase PRMT6 is a nuclear enzyme displaying unique substrate specificity[END_REF][START_REF] Miranda | PRMT7 is a member of the protein arginine methyltransferase family with a distinct substrate specificity[END_REF] Recent studies have indicated that alternative splicing of the PRMT1 mRNA results in the production of three mRNA species that vary at their 5Ј ends although the physiological relevance of this processing remains unclear.

The tissue distribution of mammalian PRMT expression is widespread, with many tissues expressing multiple isoforms. Within individual cells the intracellular localization of different PRMT isoforms varies, with some (PRMT1, 2, 4 and 6) being predominantly nuclear while the remainder (3 and 5) are predominantly cytosolic (Table 1). The intracellular localization of PRMT isoforms may be related to the localization of their substrate proteins and some reports suggest that it may be regulated in response to extracellular stimuli. [START_REF] Lin | The mammalian immediate-early TIS21 protein and the leukemiaassociated BTG1 protein interact with a protein-arginine N-methyltransferase[END_REF] The classification of type I and type II proteins was originally made on the basis of substrate specificity with type I methylating histones and type II methylating myelin basic protein. Since then numerous other substrates have been identified, predominantly for type I PRMT enzymes. There appears to be overlap in the protein substrates that can be methylated by the PRMT family, for example, in the case of histones. PRMT1, PRMT4 and PRMT5 have been shown to methylate histones H4, H3 and H4 respectively, [START_REF] Branscombe | PRMT5 (Janus kinase-binding protein 1) catalyzes the formation of symmetric dimethylarginine residues in proteins[END_REF][START_REF] Miranda | PRMT7 is a member of the protein arginine methyltransferase family with a distinct substrate specificity[END_REF][START_REF] Wang | Methylation of histone H4 at arginine 3 facilitating transcriptional activation by nuclear hormone receptor[END_REF][START_REF] Yadav | Specific protein methylation defects and gene expression perturbations in coactivatorassociated arginine methyltransferase 1-deficient mice[END_REF] with all three also methylating histone H2A. The known substrates of each PRMT isoform are listed in Table 1.

Physiological roles for protein-arginine methylation

Until recently, very little was known about the physiological role of methylation of arginine residues within proteins. Along with identification and cloning of PRMT1, Lin et al demonstrated that PRMT1 is able to interact with many proteins, including the early response proteins TIS21 and BTG1, both of which are thought to play a role in negatively regulating cell growth. Interaction of PRMT1 with these two proteins can in turn regulate its enzymatic activity. [START_REF] Lin | The mammalian immediate-early TIS21 protein and the leukemiaassociated BTG1 protein interact with a protein-arginine N-methyltransferase[END_REF] Protein arginine methylation may modify the activity of proteins required for transcription, [START_REF] Gary | RNA and protein interactions modulated by protein arginine methylation[END_REF] and may modulate the affinity of nucleic acid binding proteins for nucleic acids and may therefore be involved in mediating protein-RNA interactions. [START_REF] Gary | RNA and protein interactions modulated by protein arginine methylation[END_REF][START_REF] Belyanskaya | Exposure on cell surface and extensive arginine methylation of ewing sarcoma (EWS) protein[END_REF] Arginine methylation has also been implicated in the process of protein sorting [START_REF] Chen | Regulation of transcription by a protein methyltransferase[END_REF] and PRMT1 has been shown to regulate interferon-signalling pathways by altering targeting of nuclear proteins. [START_REF] Abramovich | A proteinarginine methyltransferase binds to the intracytoplasmic domain of the IFNAR1 chain in the type I interferon receptor[END_REF] PRMT1 is also required for the activation of the transcription factor STAT1 following interferon stimulation of cells. [START_REF] Mowen | Arginine methylation of STAT1 modulates IFNalpha/beta-induced transcription[END_REF] PRMT1 has co-activator function through methylation of histone H4 [START_REF] Wang | Methylation of histone H4 at arginine 3 facilitating transcriptional activation by nuclear hormone receptor[END_REF] and, similarly, PRMT4 via methylation of histone H3 can stimulate transcriptional activation by nuclear receptors in combination with the p160 family of co-activators. [START_REF] Chen | Regulation of transcription by a protein methyltransferase[END_REF] PRMT4 was originally noted to interact with glucocorticoid receptor interacting protein 1 (GRIP1) [START_REF] Chen | Regulation of transcription by a protein methyltransferase[END_REF] and, together with PRMT1, has also been found to interact with the p160 family of co-activators and can act in synergy with PRMT1. [START_REF] Koh | Synergistic enhancement of nuclear receptor function by p160 coactivators and two coactivators with protein methyltransferase activities[END_REF] The ability of PRMT1 and PRMT4 to act as coactivators for nuclear receptors has led to the suggestion that acetylation and methylation may co-operate with one another in the regulation of histone function. [START_REF] Chen | Regulation of transcription by a protein methyltransferase[END_REF][START_REF] Koh | Synergistic enhancement of nuclear receptor function by p160 coactivators and two coactivators with protein methyltransferase activities[END_REF][START_REF] Lee | PABP1 identified as an arginine methyltransferase substrate using high-density protein arrays[END_REF] PRMT1 has been shown to act in synergy with acetylation on histone H4, [START_REF] Wang | Methylation of histone H4 at arginine 3 facilitating transcriptional activation by nuclear hormone receptor[END_REF] suggesting a role for protein-arginine methylation in the modulation of chromatin structure and gene transcription. In support of this suggestion, PRMT4 synergises with p300 as nuclear receptor coactivators. [START_REF] Lee | PABP1 identified as an arginine methyltransferase substrate using high-density protein arrays[END_REF][START_REF] Chen | Synergistic, p160 coactivatordependent enhancement of estrogen receptor function by CARM1 and p300[END_REF] PRMT4 may also play a role in the regulation of mRNA stability as PRMT4 can methylate the mRNA binding protein HuR. Methylation of HuR promotes its binding to the 3Ј untranslated regions of certain mRNAs, resulting in the stabilization of the message and increased protein expression. [START_REF] Li | Lipopolysaccharide-induced methylation of HuR, an mRNA-stabilizing protein, by CARM1. Coactivator-associated arginine methyltransferase[END_REF] The development of a PRMT1 knockout mouse has allowed the identification of possible physiological roles for protein methylation. Pawlak et al demonstrated that the PRMT1 homozygous null mutant mouse has an embryonic lethal phenotype, thus suggesting a role for PRMT1 in the early stages of development in mice. [START_REF] Pawlak | Arginine N-methyltransferase 1 is required for early postimplantation mouse development, but cells deficient in the enzyme are viable[END_REF] PRMT4 is required for morphological skeletal muscle differentiation by acting as a co-activator for myocyte enhancer factor-2 mediated gene transcription. [START_REF] Chen | The coactivator-associated arginine methyltransferase is necessary for muscle differentiation: CARM1 coactivates myocyte enhancer factor-2[END_REF] Taken together these studies indicate that the synthesis of asymmetric methylarginine residues is a highly regulated process. Indeed, protein methylation has been suggested to be analogous to protein phosphorylation in the regulation of protein function. [START_REF] Clarke | Protein methylation[END_REF] Recent data suggest that some methylated arginine residues, particularly those found within histone tails, may be demethylated in a reaction catalysed by protein arginine deiminase. [START_REF] Wang | Human PAD4 regulates histone arginine methylation levels via demethylimination[END_REF] However, it appears that for many proteins the reversal of the effects of arginine methylation may require proteolysis of the methylated protein and new protein synthesis. Proteolysis of proteins containing methylarginine residues leads to the release of free methylarginines into the cytoplasm. [START_REF] Kakimoto | Isolation and identification of N-G,N-G-and N-G,NЈ-G-dimethyL-arginine, N-epsilon-mono-, di-, and trimethyllysine, and glucosylgalactosyl-and galactosyl-delta-hydroxylysine from human urine[END_REF] Many of the nuclear proteins that have been identified as substrates for type I PRMTs are highly abundant and contain clusters of methylarginine residues, which account for a significant proportion of the protein. For example, the nuclear protein fibrillarin contains ~4 mol% ADMA and the hnRNP complex contains ~1 mol% ADMA. Proteolysis of such proteins would liberate significant amounts of free asymmetric methylarginine residues into the cytoplasm.

Inhibition of NOS by asymmetric methylarginines

The IC 50 for L-NMMA on all three isoforms of NOS is in the order of 2-5 M. [START_REF] Vallance | Accumulation of an endogenous inhibitor of nitric oxide synthesis in chronic renal failure[END_REF] ADMA is also an effective inhibitor of NOS and is equipotent with L-NMMA. SDMA has no effect on NOS. Inhibition of NOS activity by L-NMMA is reversible by addition of arginine, however, the stoichiometery in biological systems is not 1:1 and an excess of arginine is required to reverse inhibition caused by L-NMMA or ADMA. In the presence of L-NMMA or ADMA the apparent K m of NOS for arginine increases. [START_REF] Macallister | Nitric oxide in essential and renal hypertension[END_REF] It has also been suggested that L-NMMA may irreversibly inhibit NOS under certain conditions [START_REF] Olken | NG-methyl-L-arginine functions as an alternative substrate and mechanism based inhibitor of nitric oxide synthase[END_REF] and that when arginine concentrations are very low L-NMMA can cause eNOS to generate oxygen free radicals, [START_REF] Olken | NG-methyl-L-arginine functions as an alternative substrate and mechanism based inhibitor of nitric oxide synthase[END_REF] although whether this occurs in vivo remains to be demonstrated.

Circulating levels of ADMA in healthy individuals are in the 0.5-1.0 M range but in an increasing number of disease states higher levels have been reported (Table 2). Initial observations of increased methylarginine concentrations came from studies of individuals with renal failure. Methylarginines are eliminated from the body by a combination of renal excretion and metabolism. In situations of renal failure, methylarginine excretion is decreased and concentrations of both ADMA and SDMA are elevated to levels as high as 10 M. These initial observations from renal failure cohorts have now been extended to cover a wide range of disorders, including a number in which reduced NO generation has been suggested to play a role in pathology.

Summary

An increasing volume of literature now suggests that the production of methylarginine is actively regulated. Intracellular and plasma concentrations of methylarginines are determined by the activity of synthetic and metabolic pathways and therefore misregulation of either might result in increased levels of free methylarginine. Free asymmetric methylarginines compete for the active site of NOS and may account for reduced NO generation in some disease states (Figure 3). Members of the PRMT family of enzymes are clearly key determinants of ADMA production in vivo, however isoformspecific molecular, pharmacological and biochemical reagents will be required fully to elucidate the role of these enzymes in the regulation of ADMA production in physiological and pathophysiological states.

9 Figure 1

 91 Figure 1 Structure of L-arginine and endogenously produced methylarginines. Only asymmetrically methylated arginines (L-NMMA and ADMA) are nitric oxide synthase inhibitors.

Figure 2

 2 Figure 2Methylation of arginine residues in proteins by protein-arginine methyltransferases (PRMTs). Arginine residues (®) in proteins that lie within appropriate consensus sequences can be post-translationally methylated by the action of PRMTs. S-adenosyl methionine (SAM) is the methyl donor in these reactions and S-adenosyl homocysteine (SAH) is produced.

Figure 3

 3 Figure 3 Proposed model for the regulation of intracellular asymmetric methylarginine and NO synthesis. Free arginine is metabolized to nitric oxide (NO) and citrulline by nitric oxide synthase (NOS). Arginine incorporated into proteins during protein synthesis can be methylated by type I PRMTs to generate asymmetric methylarginines (L-NMMA and ADMA), which are subsequently released by proteolysis. Free intracellular L-NMMA and ADMA are competitive inhibitors of NOS. Asymmetric methylarginine is metabolized by dimethylarginine dimethylaminohydrolase (DDAH) to citrulline. Citrulline can be converted back to arginine in a two step reaction catalysed by enzymes of the urea cycle.

  All PRMTs

			References	Tang et al 1998 18	Belyanskaya et al 2001 26	Chen et al 2002 34		Frankel et al 2002 21		Tang et al 1998 18	Frankel et al 2002 21	Chen et al 2002 34				Chen et al 1999 19	Frankel et al 2002 21	Li et al 2002 32	Branscombe et al 2001 20	Wang et al 2001 23	Frankel et al 2002 21				Miranda et al 2004 22
			Comments	Predominant in	mammalian cells, 3	splice variants		Contains SH3 domain	Interacts with ER␣	Contains zinc finger	domain, forms	homo-oligomers				Interacts with CBP/p300	and GRIP1		Forms homo-oligomers		First to automethylate				Contains 2 putative	AdoMet binding motifs
		Intracellular	distribution Substrates	Predominantly Histone H4, histone H2a,	nuclear ILF3, TIS21, BTG2,	hnRNPA1, hnRNPA2,	PABP2, Sam68	Nuclear E1B-AP5		Predominantly HnRNP A1, hnRNP A2,	cytosolic PABP2					Predominantly PABP1, p300, histone H3,	nuclear histone H2A, HuR		Predominantly MBP, smD1 and D3,	cytosolic histone H4, histone H2A	Predominantly Itself, NpI3, GAR	nuclear			? ?
	Table 1 Properties of mammalian PRMTs.	PRMT	type Name Tissue distribution	I PRMT1 Heart, testis Ͼ brain, kidney,	liver, muscle, placenta,	small intestine, spleen,	stomach, lung, colon (human)	I PRMT2/ ?	HRMT1L1	I PRMT3 Adrenal, kidney, ovary,	thyroid, brainstem,	pituitary Ͼ heart, small	intestine, testis, cortex Ͼ liver,	lung, thymus, cerebellum,	hippocampus (rat)	I PRMT4/ Heart, testis Ͼ brain, kidney,	CARM1 liver, muscle, spleen,	stomach, lung (mouse)	II PRMT5/ ?	JBP1	I PRMT6 Ͼ brain, heart, Kidney, testis	liver, muscle, placenta, small	intestine, spleen, stomach,	lung, colon	II PRMT7 ?
	Vascular Medicine 2005; 10: S3-9

BTG, B-cell translocation gene; CARM, coactivator-associated arginine methyltransferase; CBP, creb binding protein; E1B-AP5, adenovirus type 5 early 1B protein associated protein 5; E Rol, oestrogen receptor alpha; GAR, glycine-and arginine-rich N-terminal region of fibrillarin; GRIP1, glucocorticoid receptor interacting protein 1; HnRNP, heterogenous nuclear ribonuclear protein complex; HRMT, human arginine methyltransferase; HuR, embryonic lethal abnormal visual (ELAV) RNA binding protein; ILF3, interleukin enhancer binding factor 3; JBP, Janus kinase-binding protein; MBP, myelin basic protein; Np13, nuclear protein 13 kDa; PABP, poly(A)-binding protein; Sam68, src-associated substrate during mitosis 68 kDa; TIS, TPA inducible sequence.

Vascular Medicine 2005; 10: S3-9