How do Consumers Search for and Appraise Information on Medicines on the Internet ? A Qualitative Study Using Focus Groups Background Many consumers use the Internet to find information about their medicines . It is widely acknowledged that health information on the Internet is of variable quality and therefore the search and appraisal skills of consumers are important for selecting and assessing this information . The way consumers choose and evaluate information on medicines on the Internet is important because it has been shown that written information on medicines can influence consumer attitudes to and use of medicines . Introduction Consumers frequently use the Internet as an information source and it has been reported that 80 % of adult Internet-users have accessed it for general health information -LSB- 1 -RSB- . More specifically , 36 % of Internet-using consumers have used the Internet as a source of information on medicines -LSB- 1 -RSB- . It is broadly acknowledged that health information on the Internet is of variable quality as evidenced by the large number of studies that have explored the quality of consumer health information on the Internet -LSB- 2 -RSB- . This is to be expected because the Internet is a free medium . It has also been widely postulated that consumers searching for health information are in danger of being harmed by poor-quality information even though there is little evidence of this -LSB- 3 -RSB- . A consumer 's risk for encountering poor-quality health information is purportedly related to the proportion of poor-quality information on the Internet and the consumer 's ability to filter out this information -LSB- 2 -RSB- . As the quality of information on the Internet can not be controlled , the more-imperative issue is the ability of consumers to search through information and assess its quality so they are able to avoid untrustworthy information -LSB- 4 -RSB- . An Australian study suggested that consumers found it difficult to describe how they distinguished good-quality information on medicines from poor-quality information on medicines on the Internet -LSB- 5 -RSB- . However , this study was limited by a small -LRB- N = 9 -RRB- , select sample and did not explore in-depth the way consumers searched for and selected information on medicines . There is little information concerning consumer Internet-search behavior for health information . One study reported that participants mainly select Web sites that looked and read professionally and preferred understandable Web sites from official sources that used scientific references -LSB- 6 -RSB- . When participants were observed while searching for health information on the Internet , it was found that they mainly used search engines and were described as having `` suboptimal '' search skills -LSB- 6 -RSB- . This study reported that participants did not find blatantly-incorrect health information in their searches -LSB- 6 -RSB- . This indicates that they had used selection criteria to decide on the Web sites , though the criteria were not fully described in this paper . Consumer use of information on medicines is an important issue because written information on medicines has been shown to influence consumer attitudes towards their medicines , and affect their medicine-taking behavior -LSB- 7 -RSB- . Furthermore , medicines , unlike general health issues , have overtly-commercial imperatives , which may influence the information available . Since the Internet has become a common source of information on medicines , it is important to identify the way consumers are using it . Therefore the aim of this study was to explore consumer use of Internet-based information on medicines . In particular , the objectives were to : examine consumer attitudes to the availability and quality of Internet-based information on medicines ; explore consumer reasons for using this information ; explore consumer experiences in searching for and appraising information on medicines ; investigate the self-reported impact and application of this information . This paper will present results from the broader study on consumer experiences in searching for and appraising Internet-based information on medicines . Methods Selection of Method Focus groups were selected to address the study aims because they are useful for time-efficient , in-depth exploration of issues surrounding topics where there is little information -LSB- 8 - 10 -RSB- . Since there is little known about how consumers use Internet-based information on medicines , focus groups were an ideal method for exploring this issue . The results of focus groups are not intended to be statistically generalizable , but are used to reveal the range of consumer opinions and attitudes . Research Instrument An interview guide consisting of general themes constructed from the literature was prepared -LRB- Table 1 -RRB- . This paper focuses on results ensuing from the exploration of themes 4 , 5 , and 6 . The interview guide was composed of open-ended questions that addressed various issues pertaining to consumer use of Internet-based information on medicines ; the questioning route was designed to stimulate discussion -LSB- 11 - 13 -RSB- . Table 1 Themes for focus group interview guide * General opinions about the Internet as a source of information on medicines . Experiences in using the Internet to seek information on medicines . Reasons for seeking information on medicines . The methods and process of searching for information on medicines . Opinions and critique of the information found . Experiences in the evaluation of the quality of Internet-based information on medicines . Feelings after reading the information . Actions taken as a result of reading the information . Perceived benefits and drawbacks of the Internet as a source of information on medicines * This paper focuses on results ensuing from the exploration of themes 4 , 5 , and 6 . The interview guide and questioning route was pretested with a convenience sample of consumers -LRB- N = 13 -RRB- to test for interpretation , appropriateness , and comprehensiveness , and to establish face and content validity . No significant changes were made to the interview guide or questioning route as a consequence of this pretest . Participant Recruitment After approval was granted by the Human Research Ethics Committee of The University of Sydney , participants were enlisted for the focus groups by a recruitment agency . Participants were recruited from the agency 's database of consumers across metropolitan Sydney , Australia via telephone using a screening questionnaire . Consumers were deemed to be eligible for this study if they had sought Internet-based information on medicines in the preceding 12 months . This bounded reference period was applied to allow for a suitable recall of past events -LSB- 14 -RSB- while also allowing enough time for consumers to have used the Internet for this purpose . Inclusion criteria required that participants were 18 years of age or over , did not require a translator to take part in focus group discussions , did not have training as a health professional , and did not have specialist Internet training . Participants were financially reimbursed for their time and travel expenses . Study Design Six focus groups were conducted in a number of locations around metropolitan Sydney in March to May 2003 . To approximate a representative cross section of consumers , participants were recruited with the intention of including subjects from both genders and across different age groups . Focus groups were age stratified to achieve a level of homogeneity within each group . The use of stratification may increase congruency between participants , thereby allowing a more comfortable discussion -LSB- 11,15 -RSB- . Eight persons were recruited for each focus group to ensure that groups were large enough to motivate a discussion , yet small enough allow for all opinions to be heard -LSB- 11 -RSB- . The number of groups needed was not determined beforehand because data was collected until saturation occurred -LRB- the point where no new themes emerged -RRB- -LSB- 10 -RSB- . In this study , saturation occurred by the sixth focus group . The focus groups were facilitated by a skilled moderator while 2 assistant moderators observed and took notes . The group discussions were 1 to 1.5 hours in duration and were digitally sound recorded after permission was obtained from all participants . The recordings were transcribed verbatim . Participants also completed a demographics questionnaire that collected data on Internet usage . Data Analysis The verbatim transcripts were entered into NVivo qualitative software -LSB- 16 -RSB- and thematically content analyzed using a grounded theory approach . The grounded theory approach is an inductive approach to analyzing qualitative data , where ideas and emerging themes are systematically coded to generate theory -LSB- 17 -RSB- . Results This paper presents participants ' responses to themes 4 , 5 , and 6 -LRB- Table 1 -RRB- . Responses to other themes are currently unpublished . Demographics Forty-six consumers participated in this study . The age of the participants ranged from 18 to 67 years , with a median of 41 years -LRB- interquartile range , 21 years -RRB- and a mean of 41.7 years -LRB- standard deviation , 12.7 years -RRB- . Fifty-seven percent of the participants were female . The majority of the participants were employed full-time -LRB- 58.7 % -RRB- and about a fifth were either retired or full-time homemakers . Almost half the sample -LRB- 47.8 % -RRB- had occupations that could be classified as managers , professionals , or associate professionals -LSB- 18 -RSB- . A high proportion of the sample -LRB- 65.2 % -RRB- had completed further educational qualifications beyond high school , and 23.9 % of the sample had a bachelors or postgraduate degree . Data on participant usage of the Internet is presented in Table 2 . The majority of participants had a few years experience in using the Internet and over half had accessed it from both their home and workplace . In addition to using the Internet for information on medicines , most participants also used it for general health information and for services such as e-mail . Data on participant usage of the Internet for information on medicines is presented in Table 3 . In addition to using the Internet , many participants also reported using other media such as magazines for information on medicines . This variety of information sources has also been seen in another Australian study on consumer use of Internet-based general health information -LSB- 19 -RSB- . Even though most participants -LRB- 82.6 % -RRB- were seeking information for themselves , many reported also searching for other family members . This was also reflected in the aforementioned Australian study that showed that 63 % of Internet-using consumers sought health information mainly for themselves -LSB- 19 -RSB- . Table 3 Participant usage of the Internet for information on medicines -LRB- N = 46 participants -RRB- Characteristic Usage Frequency , Number of Participants Relative Frequency , -LRB- % of Participants -RRB- Media sources of information on medicines -LRB- more than one category could be selected -RRB- Internet Magazines Television Books Radio 46 31 23 22 9 100.0 67.4 50.0 47.8 19.6 Person that Internet medicine information was used for -LRB- more than one category could be selected -RRB- Self Spouse/partner Child Parent Another relative Friend 38 24 19 17 13 6 82.6 52.2 41.3 37.0 28.3 13.0 Health categories for which information on medicines had been sought for -LRB- more than one category could be selected -RRB- Allergies Arthritis/joint pain Asthma Cancer Skin disorders Hormones Other miscellaneous Child health Diabetes High cholesterol Immunization Pain and injury High blood pressure Mental health Digestion/stomach disorders Infections Migraine Osteoporosis Alzheimer 's disease Dementia 20 14 14 13 12 11 11 10 10 9 9 9 8 8 6 6 6 6 5 5 43.5 30.4 30.4 28.3 26.1 23.9 23.9 21.7 21.7 19.6 19.6 19.6 17.4 17.4 13.0 13.0 13.0 13.0 10.9 10.9 Table 2 Participant usage of the Internet -LRB- N = 46 participants -RRB- Characteristic Usage Frequency , Number of Participants Relative Frequency , % of Participants Length of experience in the use of the Internet More than 5 years 4 to less than 5 years 3 to less than 4 years 2 to less than 3 years 1 to less than 2 years Less than 1 year 17 13 7 4 4 1 37.0 28.3 15.2 8.7 8.7 2.2 Location of Internet access Home and work Home only Work only 25 16 5 54.3 34.8 10.9 Activities that the Internet is used for -LRB- more than one category could be selected -RRB- Information on medicines E-mail Health information Travel information/booking Banking/financial services News , weather , sport Job or study related research Real estate Shopping -- product research Games and hobbies Chat or instant messaging Shopping -- purchasing Purchasing medicines 46 45 43 40 36 34 34 33 33 26 22 19 7 100.0 97.8 93.5 87.0 78.3 73.9 73.9 71.7 71.7 56.5 47.8 41.3 15.2 Searching for Internet-Based Information on Medicines Search Engines All participants had used a search engine to find information on medicines . Most participants had a single favorite search engine that they would always use , but a few reported using more than one search engine to find the information they required . The choice of search engines was determined by many different factors ranging from the default search engine on their browser to active selection based on self-developed criteria . Numerous participants were influenced by the search engine that was used by coworkers , for example : Group 4 , Participant 8 I saw it on this guy 's computer and ... I thought ` Oh , I 'm going to use this ' . That 's how I started it at work . Some participants also reported that their browser automatically defaulted to a certain search engine and a few participants were unable to identify the search engine they used , for example : Group 3 , Participant 6 Could n't tell you -LSB- the search engine -RSB- really . I just log on and use whatever comes on . Many participants used search engines recommended by family and friends . There were certain determinants that led some participants to actively choose a specific search engine . These included perceptions of the credibility of the search engine , ease of use , relation with services such as e-mail , and a lack of advertising . These determinants did not necessarily include perceived quality of the information on medicines obtained through their use . A few participants reported using AltaVista -LSB- 20 -RSB- because they thought it had an educational advantage , for example : Group 1 , Participant 1 It 's got an educational edge , that 's my experience . When I was at university doing my second degree , that was one that was sort of promoted as credible I suppose . Some participants preferred to use Ask Jeeves -LSB- 21 -RSB- because they could enter the searches in a question or statement format rather than using search terms . Many participants reported using Yahoo! -LSB- 22 -RSB- because it appeared as a default homepage , was used as a personal e-mail account , or was advertised through other media . Yahoo! and Google -LSB- 23 -RSB- were also said to be useful for Australian-only searches . Google was undoubtedly the search engine the majority of participants used most and preferred . This was especially true of the younger participants . The common perception was that Google appeared to be straightforward and did not focus on advertising , for example : Group 4 , Participant 6 It 's just got less -LSB- rubbish -RSB- . It seems to be direct to what you want . I think that other -LSB- search engines -RSB- always have these categories and they always have suggestions for buying things and stuff like that but Google 's pretty much straight to the point . It 's simple . Participants also commented that this search engine was useful for suggesting spelling corrections when errors were made , as medicine names were sometimes difficult to spell . A few participants reported preferring Google as their search engine of choice specifically for health-related searches but were unable to explain reasons for their preference . Other search engines used by participants were metasearch engine Dogpile -LSB- 24 -RSB- , Australian metasearch engine Search66 -LSB- 25 -RSB- , Australian-based search engine Web Wombat -LSB- 26 -RSB- , and ninemsn -LSB- 27 -RSB- , the Australian-based access to search engine MSN Search -LSB- 28 -RSB- . Many participants who used metasearch engines were unaware of the difference between these and normal search engines . Generally , although a variety of search engines were used by participants when seeking information on medicines , the majority of participants used the same few dominant search engines . Participants generally preferred search engines with less advertising , and would continue to use the same search engine if they were successful in their searches . Most participants used the same search engine that they used for nonhealth information , and were usually influenced by what was used by friends , family , and colleagues . Search Processes Participants displayed a large variation in the process of searching for information on medicines . Most participants found information by typing the name of the medicine -LRB- drug name or brand name -RRB- into the search engine . A few participants felt this was the only way of finding information on a medicine , for example : Interviewer How do you put in your searches ? Group 6 , Participant 2 Medicines are really specific to just the name . Other participants reported looking for broader information , for example : Group 1 , Participant 2 I often use a more general -LSB- search -RSB- . I might use something like ` women 's health ' or something . And I like to see a whole range of things ... rather than targeting specifically ... and then I choose within that . The information found through this type of search was said to be less specific to one medicine and had more general or comparative information . Some participants used more-advanced search techniques such as quotation marks , phrases , and extra words to narrow down their searches . They displayed an understanding of how these techniques helped to focus their searches , for example : Group 4 , Participant 6 If you type it in with quotation marks , it 'll search for those words together whereas if you type them separately , it 'll just search for them anywhere . Participants reporting advanced skills were generally observed to be those who were younger or those who had greater experience of the Internet through work or study . However , it was clear that search skills varied significantly . The following interchange illustrates the mixed levels of understanding as to how search engines work : Group 5 , Participant 4 -LSB- You need to -RSB- ask a specific question ... ` What are the side effects ? ' rather than typing in ` penicillin ' . Participant 6 Yeah , you really have to do a whole sentence . A whole statement . Participant 3 I would type in ` penicillin side effects ' . Participant 4 ` Then it could hit on ` penicillin ' or it could hit on ` side effects ' . The uninformed way in which some participants agreed upon what they considered to be optimal search skills was obvious in the group discussions . The majority of participants in this study who reported searching using less-than-optimal techniques -- such as typing in whole questions -- tended to be nonworkers , for example , full-time homemakers or retirees . The search skills of participants varied widely and these differences may affect the resulting information that participants encounter . Searching via a search engine however , was not the only way of finding information on the Internet on medicines . Other Methods of Finding Internet-Based Information on Medicines Some participants mentioned ways of finding information on medicines in addition to using search engines . A few participants said that they guessed the Web sites of medicines by typing the name of the medicine in the address bar in the format of www . -LSB- brand name or drug name -RSB- . com . Several participants found information on medicines from Web sites recommended by family and friends , and from seeing advertisements in seniors ' and health publications . Some reported bookmarking favorite Web sites for future reference and a few subscribed to mailing lists at health-related Web sites . One participant described searching for information on medicines using online journals . Although aware that the information was not aimed at consumers , this participant still chose to use this means to search for pertinent information on medicines : Group 2 , Participant 2 I actually searched via ... the professional journals ... And I guess that was a little bit harder to do it that way because ... reading through the journals was quite difficult . I tend to just go to the abstracts . Participants reported using a variety of search skills to obtain information on medicines . However , the important issue was how they selected and appraised the information . Appraising Internet-Based Information on Medicines Selecting Internet-based Information on Medicines Participants described different ways of choosing which Web site to visit when selecting from the numerous results obtained from using a search engine . Some worked down the list of results from the first one while others looked for keywords in the Web site descriptions or for the Web site 's recency . Often participants made a judgment based on the URL -LRB- Web page address -RRB- of the result , for example : Group 4 , Participant 1 I actually like looking at the actual web address , just seeing how professional it is . Like if it 's some silly thing , I wo n't bother going into it . Many participants also reported looking for indicators in the Web site address to determine whether it belonged to a government , a university , an official organization , or a pharmaceutical company . Even though most participants said they would not go beyond the first page of the search results , one expressed the opinion that the best information was in the middle of the results and not on the first few pages . This participant had the erroneous opinion that the first pages of results are older and that results appeared mainly in the order in which the information had been created . Many participants reported looking for the country of origin of the information and preferred information generated from their country of residence , for example : Group 4 , Participant 2 If I 'm searching for a medication ... and it brought up some things and I noticed it was in Australia , I click on that . These participants felt that Australian information would be more applicable to them and professed an awareness of health-setting issues such as differences in the brand names and availability of medicines in different countries . However , others had more confidence in United States-based information because they believed that this was where most new research was undertaken . It was clear that most participants did not pay conscious attention to how they selected Internet-based information on medicines , with one referring to the process as `` a vibe '' that you obtain through experience . Another described this as a feeling that `` things have a look of credibility . '' Similarly , many participants had trouble in articulating their selection process , for example : Group 5 , Participant 3 I find that sometimes I get to a site and I think ` Gee , this is a good site , but I do n't know how I got there . ' You know what I mean ? You fluke it . Despite the inability of many participants to express how they selected information on medicines , many were able to express what they would not select . Participants reported quickly rejecting sites that were slow to load , sites that contained too many graphics , and sites that had pop-up advertisements . The process of selecting information on medicines varied among the participants . It appeared that all participants had their own criteria for selecting and rejecting information which may or may not appear logical to others . Credibility of the source , however , appeared to be a common determinant in the criteria of all participants . Credibility of the Source of Internet-Based Information on Medicines Participants expressed conflicting opinions about the credibility of the source of Internet-based information on medicines . Many participants regarded information produced by pharmaceutical companies to be the `` official '' information on a medicine and therefore trusted this the most , while many others were suspicious of a possible information bias , for example : Group 1 , Participant 7 If you 're looking at -LSB- a pharmaceutical company website -RSB- , they 've got factories throughout the world , they 're a pretty good company so ... you know that they 've done so much research it 's credible information . Group 1 , Participant 6 If it 's a pharmaceutical company , they 're gon na put a good stance on their drug . Many other participants preferred information that originated from what they considered to be impartial and reputable sources such as government , professional , or disease-focused organizations , or university Web sites . A few participants also reported looking for credentials such as the author 's qualifications when assessing the credibility of the information provider . A small number of participants preferred information written by other consumers who had personal experiences in taking the medicine . However , most participants expressed that they would be less likely to trust information on medicines generated by other consumers , for example : Group 1 , Participant 6 There are chat rooms ... if you 've ever been prescribed such and such a medication ; you 'll get people from all around the world ... Participant 2 Do you not find that a bit dangerous because everything is rather specific to each person 's body ? Participant 6 Oh yeah , but it would be comparable to having a chat with some of your friends . Some participants felt that the authorship of Internet-based information on medicines should be regulated and feared the reliability of the information because there was `` no watchdog '' for the information published on the Internet while others regarded it as analogous to the way they would trust information given in common conversation and therefore felt comfortable using information in this context . The credibility of the source of information on medicines was a strong determinant in the selection process . However , in addition to the source participants evaluated information using criteria described in the next section . Evaluating Internet-Based Information on Medicines Participants evaluated information on medicines using criteria such as the motive for the information , the language used , and the applicability to their needs . Almost all participants were skeptical to some degree of Internet-based information on medicines . Many participants professed a universal need for consumers to inherently distrust this information , and to interpret it accordingly . One participant stated that it is important to also consider why the information is on the Internet : Group 1 , Participant 6 What are the motives ? Are they conflicting , credible ? Whoever has posted it , are they trying to make a profit ? Other participants described the obviously difficult-to-believe nature of some of this information and looked for signs of conspiratorial or misleading language when deciding whether to trust the information , for example : Group 2 , Participant 8 If it says ` hazard free ' and ` completely no side effects ' , for example , I 'm more likely to disbelieve than believe that In addition to this awareness of unreliable information on medicines , many participants also expressed an understanding that the information they find may not necessarily be applicable to them and that the information should not be used at face value , for example : Group 2 , Participant 7 The thing with medicines is there 's no sort of right or wrong ... Everyone 's different , everyone 's going to have a different reaction . Group 2 , Participant 6 When you ask the doctor , they tell you ` well , -LSB- the side effects -RSB- happen but it 's not like that ' , I think what happens is that the information is not tailored for myself . It 's general information . Pertinent to this appraisal was the information-filtering process described by participants : Group 2 , Participant 4 It 's always better to try and take as much information and try and sift out what 's useless Group 1 , Participant 6 When they 're talking about people using this medicine , ` ninety-eight percent will die within five years ' ... you have to take that and filter it through a whole bunch of other variables ... and whether -LSB- the information -RSB- is not terribly well informed or completely informed . One common way in which some participants were able to filter information on medicines was to use other Web sites for comparison and cross-checking , for example : Group 4 , Participant 1 I always go to two or three sites . Although participants reported methods of evaluating information , many expressed a difficulty in their evaluation , for example : Group 2 , Participant 4 How do you -LSB- figure -RSB- out what 's useful ? Group 3 , Participant 7 How do you know what 's reliable and what 's not ? Ultimately , despite an awareness of the shortcomings and difficulties in evaluating the quality of information on medicines , all participants saw the Internet as an important resource for this information , for example : Group 1 , Participant 1 I think as patients you expect immediate information and the Internet , whether it 's credible or not , it 's the fact that people can get it . Discussion The issue of consumer use of Internet-based information on medicines is important because it has been shown that written information on medicines can be interpreted by consumers in ways that may lead to anxiety or apprehension -LSB- 7,29 - 32 -RSB- , and a refusal of prescribed medicines -LSB- 33 -RSB- . Conversely , it has been shown that written medicine information increases consumer knowledge about their medicines -LSB- 29,34 - 36 -RSB- and that well-informed consumers with an increased understanding of the purpose of their medicines may have improved compliance and satisfaction with their therapy -LSB- 29,31,37 - 40 -RSB- . However , studies on consumer use of written information on medicines have evaluated standardized information on medicines such as that produced by pharmaceutical companies , government or professional bodies , or health care practitioners -LSB- 7 -RSB- . In contrast , this study explored Internet-based information , which is neither standardized nor subject to universal quality control . Furthermore , medicines in particular are subject to commercial considerations that may have an impact on the motives for and quality of information . Therefore , the impact of Internet-based information on consumer use of medicines may differ from that reported from consumer use of standardized written information on medicines . The reported search skills of these participants were comparable to those of participants observed while searching for general health information -LSB- 6 -RSB- in that they mainly searched using simple strategies in a search engine and chose results primarily from the first page of search results . Although this similarity is not surprising , it does illustrate the overlap between appraising general health information and specifically medicines-related information . Indeed , it was not always possible for consumers in this study to speak on issues surrounding searching for and appraising information on medicines without speaking about other health-related issues . Participants in this study searched for information on medicines using a range of search techniques from simple 1-word searches and advanced techniques to suboptimal techniques . However , although some participants had little understanding of how search engines worked and possessed suboptimal search skills , a few participants described proficient search skills . Contrary to findings where consumers were observed to use information not applicable to their health setting -LSB- 6 -RSB- , participants generally reported a strong awareness of the limitations of non-Australian information due to health-setting limitations pertinent to medicines use . Participants were conscious that there was an abundance of poor-quality information on medicines on the Internet . They were also predominantly aware that information on the use of medicines and on the incidence of side effects is often based on individual factors that should not be seen as applicable to everyone . Therefore , while consumer evaluation skills have been referred to as `` meager '' -LSB- 41 -RSB- , the assumption that consumers believe everything they read does not take into account those participants who are savvy about issues such as bias , commercialism , and the lack of regulation of Internet-based information on medicines . However , the fact that many participants searched for information on a medicine by typing the brand name into a search engine would indicate that it was highly likely that they encountered the Web site of a pharmaceutical company on the first page of results -LSB- 42 -RSB- , which raises the matter of consumer ability to interpret information on medicines that may not be comparative and unbiased in nature and not aimed at an Australian audience . Even though results from this study would indicate that many participants were aware of these limitations , others still viewed a pharmaceutical company Web site as the official , and therefore exclusive , information on a medicine ; this indicates that some consumers may be unaware of or uninterested in information on medicines produced by alternate sources . Nevertheless , it has been suggested that consumers are more likely to search for alternate sources , rather than relying on product brands , as they become more experienced using the Internet -LSB- 43 -RSB- . It is clear that there was a variety of skills among participants . Many had not been conscious of some of the issues surrounding the process of searching for and appraising information on medicines and did not undertake this process in the most-constructive way . Furthermore , there have been few studies in the literature that have sought to educate consumers on strategies for effective use of the Internet for health information -LSB- 44 - 47 -RSB- . Limitations in This Study There are several important limitations in this study . First , as this information is self-reported , consumers may not actually search for and appraise information in the same way as they describe . Such a discrepancy was demonstrated when participants in an observational study were reported to be less likely to look for the sources of the information than was apparent from claims in focus groups -LSB- 6 -RSB- . However , participants in that observational study were not searching for information that they would personally use ; this may have meant that they were less concerned about the quality of the information . Second , the bounded period of 12 months in the inclusion criteria may be too long for consumers to correctly remember details of how they searched for and chose information . It might have been beneficial to actually perform a search as an activity to stimulate the participants ' memories . Third , participants in group situations may feel compelled to provide socially-desirable answers that are not necessarily accurate . In this study , we sought to minimize this by informing participants that their results would be confidential and that they were welcome to speak about anything they felt even if they disagreed with someone else . However , this does not negate the problem . Although the use of individual interviews may help to minimize this discrepancy , this method is more time-consuming and can not use group interaction for the generation of ideas . Last , certain actions are intuitive and therefore difficult to articulate . Most participants were not able to adequately describe their search and appraisal processes , which suggests that this process may largely be a form of tacit or implied knowledge . Therefore , future research needs to take into account actual observed -LRB- rather than reported -RRB- search and appraisal skills of consumers who are seeking information on medicines for their own use . Conclusion and Future Research The results of this study show that consumers may benefit from greater awareness and education on the significance of good search and appraisal skills for information on medicines so that this process is deliberate and conducted with thought rather than being random and tacit . Furthermore , there is evidence that consumers may support education that shows them how to search for information on medicines on the Internet -LSB- 48 -RSB- . However , health promotion and education needs to take into account the variety of consumer skills in both searching for and critically evaluating information . Pharmacists are in an ideal position to provide consumer training as they frequently counsel consumers on medicines -LSB- 49 -RSB- and have consumers present them with information from the Internet -LSB- 19 -RSB- . However , to successfully deliver this program , pharmacists need to be trained in these skills . Furthermore , the impact of pharmacist education on consumers ' searches for Internet-based information on medicines and appraisal of that information needs to be evaluated . Therefore , future research by this team will be on the development of a health-promotion program for pharmacists to train consumers to search for and appraise Internet-based information on medicines .

O O B O O O O B O B O O B O O O O O B I O O B O O B O O B O O B O O O O O O O B O O B O O O O O O O O O O O O B O O O O O O O B O O O B O O O B O B O O B O O O O O O O O O B O B O O O O O O O O B O O B O O O B O O B O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O B O O O B O O O O B O B O O O O O O O O O O B O O B O O O O O O O O O O O O O O O O O O O O B O O B O O O O O O O O O O O B O O O O O O O O O O O O B O O O B O O O O O O O O B O O O O O O O O O O O O O O O O O O O O B O O O O O O O O B O O B O O O O O O O O O B O O O O O O O O B O O B O O O O O O O O O O O O B O O O B O O O O O O O O O O O B O O O O O O O O O B O O O O O O O O O B O B O O B O B O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O B O B O O O O B O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O B O O O O O O B O B O O O O O O O O O B O O O O O O O O O O O O B O O O O O O O O O O O O O O B O O O O B O O O O O O B O B O O O O O O O O B O O O O O O O O O O O O O O O O O B O B O O O O O O O O O O O O O O O O O O O B O B O O O O O O O B O O O O O O O O O B O B O O O O O O O O O B O O O O O O O O O O O O O O O O O O O B O B O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O B O O B O B O B I O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O B O B O O O O O B O O B O B O O O O B O B O O O O O O O O B O B O O O O O O B O O O O O O O O O O O B O B O O O O O B O O O O O O O O O B O O O O O O O B O O O O B O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O B O O O O O O O O O O O O B O O O O O O O O O O O O O B O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O B O B O B O O O O O O O O O B O O O O O O O O O O O O O B O B O B O O O O O O O O O O O B O O O O O O O O O O O O B O B O O O O B O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O B O O O O O O O O O O O O O B O B O B O O O O O O O O O O O O O O O O O O O O O O O O B O B O O O O O O O O O B O O O O O O O O O O O O O O O O B O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O B O B O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O B O O O O O O O O O O O B O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O B O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O B O O B O B O O O O O O B O B O O O O O O B O B O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O B O O O O O O O O B O O O O B O O O O O O O O O O O O O B O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O B O O O O O O O O O O O O O B O O O B O B O O B O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O B O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O B O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O B O O O O O O O O O O O O B O B O O O O B O O O O O O O O O O B O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O B O O O B O O O O O O O O O O O O O O O O O O O O O O B O B O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O B O O O O O O O O O B O O O O O O O O O B O O O B O O O O O O O O O O O O B O O O O O O O O O B O O O O O O O O O O B O B O O O O O O O O O O O O O O O O O O B O O O O O O O O O O B O B O O B O B O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O B O B O O O O O O O O B O O O O B O O O O O O O O O O O O O O O O O O O B O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O B O O O O O O O O O B O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O B O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O B O O O O O B O O O O O O B O O O O O O O O O O O O O O O O B O O B O O O O O O O O O O O O O O O O O O O O O O O O O O B O B O O O O O O O O O B O B O O O O B O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O B O O O O O B O O O O O O O O B O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O B O B O O O B O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O B O O O O O O O B O O O O B O O O O O O O O O O O B O B O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O B O O O O O O O O O B O O O O O O O O O O O O B O B O O O O O O O O O O O O O B O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O B O O O O O O O O O O O O O O O O O O O O O B O O O O O O B O O O O O O O O O O O O B O B O O B O O O O O O O B O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O B O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O B O O O O O O O B O B O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O B O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O B O O B O O O O O O O O O O O O O O O O O O O O O O O B O O O B O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O B I O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O B O B O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O B O B O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O B O B O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O B O B O O O O O B O O O B O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O B O B O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O B O B O

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internet
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The

Use

of

Animal

Models

to

Study

Bacterial

Translocation

During

Acute

Pancreatitis

Infection

of

pancreatic

necrosis

with

intestinal

flora

is

accepted

to

be

a

main

predictor

of

outcome

during

severe

acute

pancreatitis

Bacterial

translocation

is

the

process

whereby

luminal

bacteria

migrate

to

extraintestinal

sites

Animal

models

were

proven

indispensable

in

detecting

three

major

aspects

of

bacterial

translocation

small

bowel

bacterial

overgrowth

mucosal

barrier

failure

and

disturbed

immune

responses

Despite

the

progress

made

in

the

knowledge

of

bacterial

translocation

the

exact

mechanism

origin

and

route

of

bacteria

and

the

optimal

prophylactic

and

treatment

strategies

remain

unclear

Methodological

restrictions

of

animal

models

are

likely

to

be

the

cause

of

this

uncertainty

A

literature

review

of

animal

models

used

to

study

bacterial

translocation

during

acute

pancreatitis

demonstrates

that

many

experimental

techniques

per

se

interfere

with

intestinal

flora

mucosal

barrier

function

or

immune

response

Interference

with

these

major

aspects

of

bacterial

translocation

complicates

interpretation

of

study

results

This

paper

addresses

these

and

other

issues

of

animal

models

most

frequently

used

to

study

bacterial

translocation

during

acute

pancreatitis

Introduction

Experimental

models

of

acute

pancreatitis

exist

for

almost

years

with

Claude

Bernard

first

describing

experimental

pancreatitis

by

injection

of

bile

and

olive

oil

into

the

pancreatic

duct

of

a

rabbit

Ever

since

animal

experiments

were

indispensable

in

providing

insight

in

pathophysiology

and

treatment

of

acute

pancreatitis

Experimental

studies

have

major

advantages

over

clinical

studies

such

as

the

availability

of

study

subjects

standardization

of

disease

severity

ability

to

perform

invasive

tests

extensive

tissue

sampling

and

the

possibility

to

test

prophylactic

treatment

strategies

Despite

these

advantages

some

major

aspects

of

the

pathophysiology

of

acute

pancreatitis

remain

unclear

mortality

in

severe

acute

pancreatitis

is

still

as

high

as

and

optimal

treatment

strategies

remain

a

topic

of

debate

In

Beger

et

al.

demonstrated

a

link

between

the

intestinal

flora

infection

of

pancreatic

necrosis

and

clinical

outcome

in

patients

with

severe

acute

pancreatitis

At

the

present

time

infection

of

pancreatic

necrosis

is

still

regarded

to

be

a

main

predictor

of

outcome

during

severe

acute

pancreatitis

and

bacterial

translocation

of

intestinal

flora

is

considered

to

be

the

cause

Changes

in

intestinal

motility

and

the

associated

shift

of

intestinal

flora

mucosal

barrier

function

and

the

immune

system

were

identified

as

pivotal

aspects

of

bacterial

translocation

during

acute

pancreatitis

This

has

greatly

increased

the

understanding

of

bacterial

translocation

but

better

insight

into

the

exact

mechanism

of

bacterial

translocation

and

subsequent

infection

of

pancreatic

necrosis

is

needed

to

develop

adequate

prophylaxis

and

treatment

strategies

for

patients

with

severe

acute

pancreatitis

A

multitude

of

animal

models

were

used

to

study

the

mechanism

of

bacterial

translocation

including

radiolabeling

plasmid-labeled

bacteria

or

fluorescent

beads

Despite

all

these

efforts

however

the

exact

origin

route

and

mechanism

of

bacterial

translocation

causing

infection

of

pancreatic

necrosis

are

still

unclear

The

main

reason

for

this

uncertainty

is

the

lack

of

an

ideal

animal

model

of

acute

pancreatitis

to

study

pathophysiology

of

bacterial

translocation

and

its

treatment

The

ideal

model

should

be

minimally

invasive

standardized

reproducible

and

resemble

etiology

pathophysiology

disease

course

and

outcome

of

clinical

acute

pancreatitis

including

response

to

treatment

Experimental

models

used

to

study

bacterial

translocation

in

acute

pancreatitis

and

its

treatment

all

seem

to

have

methodological

restrictions

that

complicate

the

interpretation

of

study

results

In

Foitzik

et

al.

reviewed

the

use

of

animal

models

of

acute

pancreatitis

and

their

suitability

for

evaluating

therapy

and

concluded

that

animal

models

should

be

designed

to

mimic

etiology

and

clinical

course

of

human

pancreatitis

to

increase

their

value

In

addition

we

would

like

to

discuss

the

value

animals

studies

and

experimental

models

of

acute

pancreatitis

have

in

face

of

their

interference

with

one

or

more

of

the

known

aspects

of

bacterial

translocation

intestinal

motility

and

flora

mucosal

barrier

function

or

the

immune

system

The

aim

of

this

paper

is

to

provide

useful

insights

into

the

use

of

animal

models

to

study

bacterial

translocation

during

acute

pancreatitis

in

the

light

of

current

knowledge

of

pathophysiology

Animal

Species

and

Housing

Conditions

Before

the

late

larger

laboratory

animals

such

as

dogs

were

predominantly

used

to

study

acute

pancreatitis

But

since

the

introduction

of

models

of

acute

pancreatitis

in

small

laboratory

animals

mice

or

rats

are

generally

favored

for

financial

and

ethical

or

practical

reasons

Because

of

physiological

and

anatomical

differences

between

species

choice

of

laboratory

animal

has

important

implications

on

the

study

results

and

extrapolation

to

the

human

situation

Intestinal

flora

differs

between

animal

species

largely

depending

on

dietary

demands

and

anatomical

differences

of

the

gastrointestinal

tract

and

habits

The

protein-rich

diet

of

dogs

or

cats

results

in

lower

counts

of

endogenous

lactobacilli

and

higher

counts

of

potential

pathogens

-LRB-

e.g.

clostridia

species

-RRB-

compared

to

rats

or

mice

with

fiber-rich

diets

Coprophagy

demonstrated

by

most

rodents

also

influences

intestinal

flora

resulting

in

higher

counts

of

gram-negative

bacteria

in

the

proximal

gastrointestinal

tract

Also

rats

and

mice

are

often

bred

and

kept

under

specific

pathogen-free

conditions

introducing

modifications

of

intestinal

flora

Intestinal

barrier

function

also

differs

between

species

In

an

experiment

comparing

small

intestinal

permeability

between

humans

and

rats

significant

interspecies

variation

in

urinary

recovery

of

orally

delivered

mannitol

was

observed

Anatomical

differences

between

species

should

also

be

considered

The

relative

size

of

the

jejunum

ileum

cecum

and

colon

of

different

laboratory

animals

can

influence

origin

and

route

of

bacterial

translocation

during

acute

pancreatitis

In

humans

retroperitoneal

connections

between

the

intestines

and

pancreas

can

greatly

affect

the

clinical

course

of

the

disease

Similar

to

humans

the

dog

pancreas

is

situated

retroperitoneally

Rat

and

mouse

pancreata

however

are

almost

fully

enveloped

by

peritoneum

resembling

a

more

intraperitoneal

localization

Variation

in

retroperitoneal

connections

between

intestines

and

the

pancreas

offers

different

routes

for

bacteria

to

translocate

without

being

exposed

to

intraperitoneal

immune

cells

Experiments

using

small

animals

-LRB-

e.g.

mouse

or

rat

-RRB-

usually

incorporate

a

larger

number

of

animals

compared

to

experiments

with

large

laboratory

animals

-LRB-

e.g.

cat

or

dog

-RRB-

The

use

of

a

larger

number

of

small

laboratory

animals

improves

statistical

power

of

an

experiment

On

the

other

hand

the

use

of

larger

animals

could

resemble

human

pathophysiology

better

but

a

smaller

number

of

animals

means

lower

statistical

power

and

increased

potential

false

negative

or

false

positive

results

Models

of

Acute

Pancreatitis

An

abundance

of

animal

models

of

acute

pancreatitis

is

used

to

investigate

bacterial

translocation

Only

models

most

frequently

used

for

this

purpose

will

be

discussed

Baseline

characteristics

of

the

discussed

models

and

their

potential

effects

on

intestinal

flora

mucosal

barrier

and

immune

function

are

summarized

in

Tables

and

Table

of

Several

Animal

Models

of

Acute

PancreatitisModelAnimal

SpeciesPancreatic

NecrosisPancreatic

InfectionMortalityInvasivenessDuodenal

ratYes/NoLittleLowMinimalDuct

to

highLaparotomyDuct

perfusion

of

Bacterial

Translocation

and

Potential

Confounding

Factors

of

Animal

ModelsAspectConfounding

FactorModelIntestinal

motility

and

floraAnimal

speciesPotentially

all

modelsHousing

conditions

-LRB-

SPF

-RRB-

Potentially

all

modelsDietCDE

dietAnalgesicsInvasive

modelsLaparotomyInvasive

modelsBile

flowDuct

ligationCeruleinCerulein

modelsIntestinal

manipulationInvasive

modelsMucosal

barrier

functionStressPotentially

all

models

DietCDE

dietAnestheticsInvasive

modelsPancreatic

proteasesDuct

ligationIntestinal

manipulation/punctureDuct

perfusionImmune

systemStressPotentially

all

modelsDietCDE

dietDisease

course/severitySpecies-dependentObstructive

jaundiceDuct

ligation

duodenal

loopIntestinal

manipulationInvasive

models

Duodenal

Loop

Closing

the

duodenal

lumen

proximally

and

distally

to

the

papilla

of

Vater

results

in

reflux

of

the

duodenal

contents

enclosed

in

the

loop

including

bile

and

pancreatic

secretions

into

the

biliopancreatic

duct

In

rats

this

leads

to

acute

pancreatitis

of

varying

severity

Discontinuation

of

the

gastrointestinal

tract

leads

to

mucosal

atrophy

and

functional

changes

to

the

mucosal

barrier

Furthermore

obstruction

of

bile

flow

into

the

intestine

was

shown

to

reduce

intestinal

motility

causing

small

bowel

bacterial

overgrowth

and

increased

bacterial

translocation

Another

major

downside

is

the

occurrence

of

reflux

of

duodenal

contents

including

bacteria

into

the

biliopancreatic

duct

These

obvious

drawbacks

of

this

model

in

experiments

concerning

bacterial

translocation

are

the

cause

of

its

limited

popularity

Ethionine-supplemented

Choline

Deficiency

Lombardi

et

al.

described

severe

acute

pancreatitis

in

young

female

mice

after

feeding

a

choline-deficient

ethionine-supplemented

-LRB-

CDE

-RRB-

diet

Acute

hemorrhagic

pancreatitis

ensues

as

well

as

diffuse

intraperitoneal

fat

necrosis

and

several

systemic

effects

such

as

acidosis

hypoxia

and

hypovolemia

In

this

model

mortality

ranges

from

to

after

days

and

can

be

controlled

by

varying

the

duration

of

the

choline-deficient

diet

To

ensure

homogeneity

and

reproducibility

sex

age

and

weight

of

the

mice

have

to

be

closely

matched

as

well

as

food

intake

of

all

animals

Apart

from

these

practical

downsides

of

the

model

systemic

complications

unrelated

to

pancreatitis

-LRB-

e.g.

parotitis

and

fatty

liver

disease

-RRB-

render

the

model

less

useful

for

investigating

systemic

events

-LRB-

e.g.

immune

response

-RRB-

of

acute

pancreatitis

Little

is

known

of

the

effect

of

ethionine

suppletion

or

choline

deficiency

on

intestinal

flora

or

mucosal

barrier

function

But

the

most

important

drawback

of

this

model

to

study

bacterial

translocation

is

the

low

incidence

of

pancreatic

infection

-LRB-

-RRB-

even

in

severe

necrotizing

pancreatitis

Biliopancreatic

Duct

Ligation

In

the

duct

ligation

model

the

common

biliopancreatic

duct

is

surgically

clipped

or

tied

at

the

sphincter

of

Oddi

complex

The

resulting

obstruction

of

pancreatic

secretions

and

potential

biliary

reflux

into

the

pancreatic

duct

produce

moderate

pancreatitis

characterized

by

edema

moderate

inflammation

and

hemorrhage

fat

necrosis

and

minimal

acinar

cell

necrosis

Only

in

the

American

opossum

does

biliopancreatic

duct

ligation

leads

to

severe

acute

pancreatitis

with

considerable

necrosis

This

model

of

acute

pancreatitis

greatly

interferes

with

the

pathophysiology

of

bacterial

translocation

Obstruction

of

bile

flow

into

the

intestine

causes

small

bowel

bacterial

overgrowth

and

bacterial

translocation

Also

exclusion

of

pancreatic

proteases

in

the

gut

lumen

alters

intestinal

permeability

Apart

from

effects

on

the

intestinal

flora

and

mucosal

barrier

function

obstruction-induced

jaundice

also

causes

impairment

of

the

immunesystem

These

effects

complicate

the

interpretation

of

bacteriological

results

to

study

bacterial

translocation

Cerulein

Infusion

Infusion

of

low

doses

of

cerulein

a

cholecystokinin

analog

enhances

production

of

pancreatic

exocrine

cell

secretions

without

cell

necrosis

In

most

species

infusion

of

supramaximal

doses

results

in

a

decrease

of

secretion

and

acute

pancreatitis

with

interstitial

edema

and

inflammatory

cell

infiltration

In

mice

cerulein

causes

severe

acute

pancreatitis

with

necrosis

of

of

acinar

cells

In

rats

and

other

animals

however

cerulein-induced

pancreatitis

is

usually

mild

and

generally

self-limiting

Moreover

pigs

are

reported

to

be

insensitive

to

cerulein

hyperstimulation

It

should

be

noted

that

cerulein

is

known

to

affect

intestinal

motility

Studies

investigating

the

use

of

cerulein

in

man

have

shown

absence

of

recognizable

migrating

motor

complexes

with

decreased

colonic

transit

time

In

general

experimental

acute

pancreatitis

is

associated

with

reduced

small

bowel

motility

resulting

in

small

bowel

bacterial

overgrowth

and

increased

bacterial

translocation

to

extraintestinal

sites

Thus

cerulein

may

interfere

with

intestinal

flora

by

altering

intestinal

motility

Investigators

should

keep

this

in

mind

when

designing

a

study

and

interpreting

study

results

Biliopancreatic

Duct

Perfusion

Duct

perfusion

models

are

currently

the

most

popular

models

of

acute

pancreatitis

Induction

of

acute

pancreatitis

involves

infusion

of

bile

bile

salts

with

or

without

bacteria

or

activated

pancreatic

enzymes

into

the

-LRB-

bilio

-RRB-

pancreatic

duct

Early

experiments

mainly

involved

dogs

but

currently

rats

are

used

most

frequently

Severity

and

reproducibility

of

acute

pancreatitis

and

ensuing

bacteriological

results

strongly

depend

on

infusate

infusion

pressure

volume

and

time

The

most

commonly

used

infusates

are

solutions

containing

various

concentrations

of

bile

salts

of

varying

hydrophobicity

Both

chemical

and

pressure

effects

of

infusion

were

suggested

to

play

a

major

role

in

the

pathogenesis

of

pancreatitis

in

perfusion

models

In

both

chemical

and

pressure-induced

pancreatitis

destruction

of

the

pancreatic

duct

mucosal

barrier

is

the

key

event

This

is

followed

by

pancreatic

edema

autolysis

reduction

of

pancreatic

blood

flow

and

in

severe

cases

destruction

of

pancreatic

parenchyma

and

formation

of

pancreatic

necrosis

Uncontrolled

pressure-related

damage

causes

variation

in

severity

of

the

induced

acute

pancreatitis

between

study

subjects

and

thus

should

be

avoided

Several

experiments

were

performed

to

assess

maximal

pancreatic

duct

pressure

before

rupture

of

the

duct

epithelium

causing

increased

and

uncontrolled

severity

of

acute

pancreatitis

Data

are

conflicting

with

rupture

pressures

varying

from

to

mmHg

A

maximum

infusion

pressure

of

to

mmHg

is

currently

accepted

for

rat

models

Perfusion

is

usually

performed

by

puncturing

the

duodenum

and

cannulating

the

papilla

of

Vater

The

introduction

of

duodenal

bacteria

through

the

papilla

of

Vater

into

the

biliopancreatic

duct

could

potentially

be

a

confounding

factor

in

transduodenal

duct

perfusion

models

It

was

demonstrated

however

that

significant

bacterial

infection

of

the

pancreas

-LRB-

colony

forming

units

per

gram

-RRB-

because

of

the

surgical

procedure

does

not

occur

Advantages

of

this

model

are

the

quick

procedure

of

acute

pancreatitis

induction

and

the

reproducibility

of

results

Other

than

duodenal

puncturing

and

intestinal

handling

during

surgery

both

potentially

affecting

mucosal

barrier

function

no

direct

effects

on

intestinal

flora

or

immune

function

are

expected

in

this

model

Biliopancreatic

Duct

Injection

and

Cerulein

Hyperstimulation

The

combination

of

retrograde

infusion

of

bile

salts

with

superimposed

cerulein

hyperstimulation

in

rats

was

introduced

by

Schmidt

et

al.

and

was

advocated

as

a

better

model

for

evaluating

therapy

Although

the

disadvantages

described

for

biliopancreatic

duct

injection

and

cerulein

hyperstimulation

all

apply

to

this

model

it

was

proven

a

very

valuable

model

to

examine

bacterial

translocation

and

treatment

strategies

The

major

advantages

are

that

histological

and

qualitative

bacteriological

results

as

well

as

reaction

to

treatment

and

disease

course

resemble

human

acute

pancreatitis

more

closely

than

other

models

Although

proven

a

very

valuable

model

potential

model-related

confounding

factors

as

described

above

should

always

be

kept

in

mind

when

interpreting

results

Disease

Course

Especially

in

the

severe

form

of

acute

pancreatitis

systemic

events

can

be

divided

into

two

phases

early

proinflammatory

and

late

immunosuppressive

In

severe

acute

pancreatitis

the

early

phase

is

associated

with

a

systemic

inflammatory

response

syndrome

-LRB-

SIRS

-RRB-

potentially

leading

to

multiple

organ

failure

and

early

mortality

The

late

phase

is

characterized

by

immunosuppression

providing

opportunity

for

infectious

complications

-LRB-

e.g.

infection

of

pancreatic

necrosis

-RRB-

associated

with

sepsis

and

late

mortality

Laboratory

animal

species

and

experimental

models

however

each

show

their

own

disease

course

of

acute

pancreatitis

Animal

models

were

mainly

used

to

investigate

the

early

phase

of

acute

pancreatitis

However

the

model

described

by

Schmidt

et

al.

seems

the

most

appropriate

to

investigate

early

and

late

systemic

complications

considering

that

both

phases

can

be

discerned

In

this

model

infection

of

pancreatic

necrosis

progresses

at

least

until

h

When

taking

into

account

that

disease

course

is

more

rapid

in

small

rodents

timing

could

well

correlate

with

data

on

the

course

of

severe

acute

pancreatitis

in

humans

as

described

by

Foitzik

et

al.

Beger

et

al.

and

Lankisch

et

al.

Severity

Pancreatic

necrosis

is

produced

in

several

animal

models

of

acute

pancreatitis

-LRB-

Table

-RRB-

On

the

other

hand

only

duct

perfusion

with

or

without

superimposed

cerulein

hyperstimulation

and

murine

CDE

models

demonstrate

mortality

comparable

to

human

necrotizing

acute

pancreatitis

Models

with

high

early

mortality

may

be

useful

to

investigate

early

phase

systemic

inflammatory

response

and

organ

failure

but

are

less

adequate

to

investigate

late

infectious

complications

and

associated

-LRB-

multiple

-RRB-

organ

failure

In

most

models

necrosis

needs

to

be

present

for

pancreatic

infection

to

occur

It

needs

to

be

noted

that

this

does

not

apply

for

the

duodenal

loop

model

in

which

reflux

of

duodenal

contents

into

the

biliopancreatic

duct

occurs

In

contrast

the

murine

CDE

model

produces

elaborate

necrosis

but

is

associated

with

very

low

rates

of

pancreatic

infection

Culturing

Controls

and

Route

of

Bacterial

Translocation

In

all

animal

models

factors

such

as

analgesia

anesthesia

or

surgical

techniques

can

influence

bacteriological

results

Morphine-like

analgesics

have

a

significant

effect

on

bowel

motility

and

cause

bacterial

overgrowth

and

translocation

to

extraintestinal

sites

The

anesthetic

pentobarbital

was

suspected

to

be

a

factor

in

promoting

bacterial

translocation

in

a

model

of

hemorrhagic

shock

Also

stress

causes

mucosal

barrier

failure

and

bacterial

translocation

Surgical

procedures

are

stressful

events

but

animal

transport

or

handling

alone

could

potentially

cause

stress-induced

bacterial

translocation

The

influence

of

stress

on

adrenaline

and

corticosteroid

levels

could

have

its

own

effect

on

the

function

of

the

immune

system

potentially

influencing

the

systemic

reaction

to

acute

pancreatitis

and

bacterial

translocation

Proper

sterile

surgical

techniques

are

very

important

when

investigating

bacterial

translocation

If

abdominal

surgery

is

involved

control

cultures

of

the

peritoneal

cavity

to

trace

surgical

contamination

are

of

special

importance

If

peritoneal

cultures

are

found

to

be

positive

extra

caution

should

be

taken

with

interpretation

of

bacteriological

analysis

of

abdominal

organs

In

case

of

surgical

contamination

or

transperitoneal

bacterial

translocation

the

peritoneal

covering

of

the

organ

samples

might

be

the

cause

of

positive

organ

cultures

not

the

bacterial

colonization

in

the

organ

itself

-LRB-

false

positive

culture

-RRB-

Puncturing

the

duodenum

in

duct

infusion

models

hypothetically

causes

spillage

of

duodenal

contents

onto

the

peritoneum

covering

all

abdominal

organs

In

rats

however

duodenal

contents

usually

have

low

bacterial

counts

mainly

consisting

of

nonpathogenic

lactobacilli

only

On

the

other

hand

a

duct

infusion

study

by

Cicalese

et

al.

reported

positive

peritoneal

cultures

at

time

of

induction

of

pancreatitis

of

to

of

the

studied

rats

Literature

review

of

different

animal

models

fairly

frequently

shows

positive

peritoneal

cultures

at

the

time

of

termination

and

organ

sample

collection

of

rats

with

acute

pancreatitis

Positive

peritoneal

cultures

are

observed

varying

from

in

minimally

invasive

models

of

acute

pancreatitis

-LRB-

cerulein

injection

CDE

diet

-RRB-

to

in

more

invasive

models

-LRB-

duct

perfusion

with

or

without

cerulein

hyperstimulation

-RRB-

Discussion

Changes

in

intestinal

motility

and

flora

mucosal

barrier

function

and

immune

response

were

established

as

pivotal

aspects

in

the

process

of

bacterial

translocation

during

acute

pancreatitis

Early

after

the

onset

of

acute

pancreatitis

neurohormonal

effects

result

in

reduced

small

bowel

motility

This

causes

stasis

of

luminal

contents

and

small

bowel

bacterial

overgrowth

with

potential

pathogens

including

Escherichia

coli

and

Enterococcus

species

The

abundant

presence

of

luminal

pathogens

forms

a

challenge

for

the

mucosal

barrier

Furthermore

pancreatitis-associated

reduced

intestinal

blood

flow

results

in

mucosal

ischemia

and

reperfusion

damage

Luminal

bacteria

normally

held

at

bay

by

the

mucosal

barrier

now

have

opportunity

to

penetrate

into

the

intestinal

epithelium

Local

intestinal

inflammation

follows

further

compromising

mucosal

barrier

function

Pancreatitis

and

ensuing

intestinal

inflammation

both

contribute

to

a

systemic

proinflammatory

response

-LRB-

SIRS

-RRB-

with

damaging

effects

on

distant

organs

If

the

systemic

response

is

severe

multiple

organ

dysfunction

syndrome

-LRB-

MODS

-RRB-

might

follow

If

the

patient

survives

the

early

phase

counterregulatory

immunological

pathways

releasing

anti-inflammatory

cytokines

result

in

a

refractory

state

characterized

by

immunosuppression

Persistent

immunosuppression

will

render

the

patient

liable

for

infection

of

pancreatic

necrosis

Multiple

organ

dysfunction

syndrome

caused

by

infectious

complications

is

considered

accountable

for

so-called

late

mortality

or

late

septic

death

Although

animal

models

were

proven

indispensable

in

acute

pancreatitis

research

model-related

problems

are

most

likely

the

reason

for

important

questions

on

pathophysiology

and

treatment

strategies

to

remain

unanswered

Current

topics

of

debate

include

the

route

and

origin

of

bacterial

translocation

and

optimal

prophylaxis

and

treatment

strategies

Several

different

routes

of

bacterial

translocation

were

described

and

have

directed

efforts

for

many

prophylactic

and

therapeutic

strategies

Webster

et

al.

showed

bacteremia

to

occur

early

after

induction

of

acute

pancreatitis

in

CDE-induced

acute

pancreatitis

suggesting

a

hematogenous

route

Likewise

rapid

passage

of

bacteria

into

the

blood

was

found

in

other

models

of

acute

pancreatitis

On

the

other

hand

Runkel

et

al.

found

bacteria

migrating

to

lymph

nodes

before

their

translocation

to

distant

sites

in

a

duct

ligation

model

suggesting

a

lymphogenous

route

Widdison

et

al.

suggested

transperitoneal

translocation

of

bacteria

originating

from

the

colon

in

a

feline

model

of

severe

necrotizing

pancreatitis

Other

study

groups

including

our

own

have

provided

proof

of

the

role

of

the

small

bowel

in

the

pathophysiology

of

bacterial

translocation

in

acute

pancreatitis

or

after

morphine

administration

The

model

of

duct

perfusion

and

cerulein

hyperstimulation

described

by

Schmidt

et

al.

was

proven

very

useful

because

it

resembles

human

disease

quite

well

considering

its

biphasic

disease

course

pancreatic

histology

moderate

mortality

and

the

bacterial

spectrum

in

pancreatic

necrosis

However

whether

a

confounder

is

introduced

by

puncturing

the

duodenum

and

cannulating

the

biliopancreatic

duct

is

unknown

Therefore

to

ensure

quality

of

the

presented

study

results

control

cultures

of

the

peritoneal

cavity

should

be

done

when

organ

samples

are

analyzed

bacteriologically

Peritoneal

bacteria

can

potentially

affect

bacteriological

analysis

of

all

abdominal

tissues

Widdison

et

al.

washed

abdominal

samples

before

analysis

but

this

is

not

commonly

performed

A

pilot

study

by

Arendt

et

al.

showed

that

washing

removed

of

intraperitoneally

injected

bacteria

Immunohistologically

localizing

bacteria

can

help

clarify

if

positive

cultures

of

abdominal

tissues

are

because

of

peritoneally

located

bacteria

or

actual

bacterial

colonization

in

the

underlying

organ

tissue

When

experimentally

evaluating

therapy

treatment

often

starts

before

induction

of

acute

pancreatitis

Obviously

this

is

an

important

reason

why

results

can

not

directly

be

translated

to

the

clinical

situation

On

the

other

hand

these

experimental

studies

provide

proof

of

principle

concerning

the

tested

therapy

If

prophylactically

successful

the

tested

treatment

strategy

might

be

beneficial

when

started

after

the

onset

of

acute

pancreatitis

and

should

therefore

be

further

investigated

On

the

other

hand

the

faster

course

of

acute

pancreatitis

in

rodent

models

provides

only

a

very

short

treatment

window

between

the

onset

of

the

disease

and

early

or

late

phase

complications

This

may

lead

to

false

negative

effects

of

the

therapy

tested

In

conclusion

animal

models

of

acute

pancreatitis

are

indispensable

tools

but

model-related

drawbacks

often

interfere

with

one

or

more

pathophysiological

aspects

of

bacterial

translocation

complicating

interpretation

of

results

When

the

ideal

model

of

acute

pancreatitis

is

not

at

hand

it

is

of

major

value

that

numerous

alternatives

are

available

But

with

each

experimental

hypothesis

special

care

should

be

taken

to

select

the

most

suitable

model

Despite

all

the

experimental

work

done

the

route

by

which

pancreatic

infection

occurs

and

gives

rise

to

septic

complications

and

mortality

has

not

yet

fully

been

elucidated

Optimal

prophylactic

and

treatment

strategies

are

also

still

widely

debated

In

the

future

animal

models

will

undoubtedly

provide

increasing

understanding

of

these

subjects

but

model-related

drawbacks

should

always

be

kept

in

mind

when

designing

a

study

or

when

interpreting

results

O O O B O O O B I O O B O O O O O O O O O O O O O O O O O O O B O B I O O O O O O O O O O O B O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O B O O O O B I O O B O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O B O O O O O O B I O O B O O O O O O B O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O B O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O B O O O O O O O O O O B I O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O B O O O O B O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O B B O O B O O O O B I O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O B I O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O B O O O O O O O O O B O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O B I O O B O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O B O O O B O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O B I O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O B O O O O O O O O O O O B O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O B I O O O O O O O O O O O O O O O O O O B O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O B O O B O O O O O O B I O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O B O O O O O O O B O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O B O B O O O O O O O O O O O B O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O B I O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O B O O O O O O O O O O O O B I O O O O O O O O B O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O B I O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O B O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O B O O O B O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O B O O O B O O O O O O O O O O O O O O O O O O O O O O O B I O O B O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O B O O O O O O O O O O O O O O O O B I O O O O O O O O O B O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O

pancreatitis
bacterial translocation
animal
model