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Home医源资料库在线期刊微生物临床杂志2005年第43卷第12期

Bacterial Characteristics in Relation to Clinical Source of Escherichia coli Isolates from Women with Acute Cystitis or Pyelonephritis and Uninfected Women

来源:微生物临床杂志
摘要:MucosalandVaccineResearchCenterGeriatricResearch,Education,andClinicalCenter,VAMedicalCenter,Minneapolis,Minnesota,andDepartmentsofMedicinePsychiatry,UniversityofMinnesota,Minneapolis,MinnesotaABSTRACTCharacteristicsdifferentiatingEscherichiacolistrainsthatcausec......

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    Mucosal and Vaccine Research Center
    Geriatric Research, Education, and Clinical Center, VA Medical Center, Minneapolis, Minnesota, and Departments of Medicine
    Psychiatry, University of Minnesota, Minneapolis, Minnesota

    ABSTRACT

    Characteristics differentiating Escherichia coli strains that cause cystitis or pyelonephritis from fecal E. coli remain incompletely defined, particularly among adult women in the United States. Accordingly, phylogenetic group, O antigens, and virulence factors (VFs) were analyzed among 329 E. coli isolates from the mid-to-late 1990s from women in the United States with acute pyelonephritis (n = 170), cystitis (n = 83), or no infection (fecal; n = 76). Compared with fecal and cystitis isolates, pyelonephritis isolates exhibited a greater prevalence of phylogenetic group B2, most virulence-associated O antigens, and most VFs and had higher VF scores. In contrast, cystitis and fecal isolates differed minimally. By stepwise multivariable logistic regression, significant (P  0.015) predictors of cystitis and/or pyelonephritis (versus fecal) included afa/dra (Dr-binding adhesins), ibeA (invasion of brain endothelium), iha (putative adhesin-siderophore), malX (pathogenicity island marker), the O75 antigen, papEF (P fimbriae), papG allele II (P adhesin variant), group B2, and sfa/foc (S and F1C fimbriae). However, virulence profiles overlapped considerably among source groups and varied greatly within each group. E. coli "clonal group A" (CGA) and the O2:K5/K7:H1 and O75:K+ clonal groups were significantly associated with cystitis and/or pyelonephritis. These findings identify potential vaccine targets, suggest that urovirulence is multiply determined, and confirm the urovirulence of specific E. coli clonal groups, including recently recognized CGA.

    INTRODUCTION

    Acute cystitis is extremely common among reproductive-age women, whereas acute pyelonephritis, while much less common, is associated with high per-episode costs and morbidity (40). Together, cystitis and pyelonephritis are major contributors to the overall health burden and costs attributable to urinary tract infection (UTI) among women (40). Better characterization of the distinctive extraintestinal pathogenic Escherichia coli (ExPEC) strains that cause most episodes of cystitis and pyelonephritis in women could conceivably help guide the development of preventive measures against these important diseases (33, 41).

    Most previous epidemiological comparisons involving E. coli urine isolates from patients with cystitis or pyelonephritis and fecal isolates from healthy controls were done with children and/or outside the United States and prior to the recent rise in antimicrobial resistance among uropathogens (1, 2, 5-7, 27, 28, 34). Since the human fecal E. coli flora can vary dramatically by locale (4, 44, 50) and since assays are now available for E. coli phylogenetic group (3) and for many more virulence factors (VFs) than were included in most previous studies (21, 24, 25), we chose to revisit this issue. Specifically, we analyzed E. coli urine isolates from women with acute uncomplicated cystitis or pyelonephritis and fecal isolates from uninfected women, as collected in the mid-to-late 1990s in the United States. We sought to identify syndrome-specific differences in the distribution of E. coli phylogenetic groups, O antigens, individual VFs, and composite virulence profiles.

    MATERIALS AND METHODS

    Subjects and isolates. The project was approved by the relevant institutional review boards. Fecal E. coli isolates were obtained in 1998 and 1999 from consenting women volunteers who did not have UTI-associated symptoms and were receiving (or were eligible to receive) health care at the University of Minnesota student health service (Minneapolis, MN). Fecal swabs were collected and processed within 48 h to isolate E. coli (12). One arbitrarily selected E. coli colony per sample was analyzed (42).

    Cystitis isolates were recovered from urine samples from consenting women volunteers who presented to the University of Minnesota student health service in 1998 or 1999 with symptoms of uncomplicated acute cystitis and who had pyuria on microscopic analysis (30). Urine samples were refrigerated until cultured (100 μl) on MacConkey agar, within 72 h of collection. Lactose-fermenting, indole-positive colonies with an appropriate colonial morphology were defined as E. coli. From the 82 samples that yielded 10 CFU/ml E. coli (46), one arbitrarily selected E. coli colony per sample was analyzed (42).

    Pyelonephritis isolates included the 170 available pretherapy E. coli urine isolates from women with acute uncomplicated pyelonephritis of mild-to-moderate severity from a recent multicenter treatment trial (1994 to 1996) (17, 48). The subjects were from 25 widely distributed U.S. locales, including five subjects from Minneapolis, MN (University of Minnesota Hospital or Student Health Service) (43).

    Phylotyping, virulence genotyping, and O typing. Isolates were tested in duplicate for the four main E. coli phylogenetic groups (A, B1, B2, and D), 31 ExPEC-associated VFs, and 13 papA (P fimbriae subunit) alleles by using established PCR- and dot blot-based assays, together with appropriate positive and negative controls (3, 21, 24, 25). The VF score was the number of VFs detected, adjusted for multiple detection of the pap and kps (capsule) operons. Such molecular characteristics have previously been shown to predict experimental in vivo virulence (15, 36). O antigens were determined by the E. coli Reference Center (University Park, PA). The O1, O2, O4, O6, O7, O16, O18, O25, and O75 antigens were regarded as UTI-associated (O-UTI) (11).

    Statistical analysis. Comparisons of proportions were tested using Fisher's exact test for unpaired comparisons and McNemar's test for paired comparisons. (For multiple-group comparisons, an initial chi-square or Fisher's exact test for heterogeneity was done, and only if this yielded a P value of <0.05 were the individual pairwise comparisons tested.) Comparisons involving VF scores were tested using the Mann-Whitney U test. (For multiple-group comparisons, an initial test for heterogeneity across groups was done using a Kruskal-Wallis one-way analysis of variance, and only if this yielded a P value of <0.05 were individual pairwise comparisons examined.) Stepwise multivariable logistic regression analysis was used to assess multiple bacterial characteristics simultaneously as predictors of source group. Cluster analysis of VF profiles was done according to the unweighted pair group method with arithmetic averaging. The resulting tree was inspected (i) to determine whether each isolate's nearest neighbor in the tree represented the same source group, an alternate source group, or (if a cluster) multiple source groups and (ii) to identify clades exclusively representing a specific source group. The threshold for statistical significance was a P value of <0.05, with a P value of <0.015 used in the multivariable models.

    RESULTS

    Phylogenetic group. The three source groups (fecal, cystitis, and pyelonephritis) differed significantly for the prevalence of phylogenetic groups A, B1, and B2 but not D (Table 1). All differences were between the pyelonephritis group versus the fecal and cystitis groups rather than between the fecal and cystitis groups. Although phylogenetic group B2 predominated overwhelmingly among the pyelonephritis isolates, it was also the most prevalent group among the fecal and cystitis isolates (Table 1).

    O antigens. The 9 UTI-associated O antigens were encountered, in descending order of frequency, as follows (with percentage of 329 isolates indicated in parentheses): O2 (19%); O6 (10%); O75 (7%); O1 and O18 (5% each); O4, O16, and O25 (3% each); O7 (2%). Overall, 185 (56%) isolates exhibited a UTI-associated O antigen. The O11/O17/O73/O77 antigens, characteristic of E. coli clonal group A (CGA) (17, 19, 30), occurred in 23 (7%) isolates. The O2, O16, and O75 antigens, and the O-UTI antigens collectively, were significantly associated with pyelonephritis, whereas the fecal and cystitis isolates did not differ significantly for any O antigen(s) (Table 1).

    Virulence factors. Of the 31 VFs sought, all but papG allele I (P fimbriae adhesin variant) and bmaE (M fimbriae) were detected in 1 isolate each (Table 2). Of the detected VFs, 21 (72%) were significantly distributed by source group. All but 3 were significantly more prevalent among pyelonephritis isolates than among fecal and/or cystitis isolates. Exceptions included the K1 kpsM (capsule) variants (most prevalent among fecal isolates) and ibeA (invasion of brain endothelium; most prevalent among cystitis isolates) (Table 2). Only these two VFs differed significantly in prevalence between the fecal and cystitis isolates, and these differences were modest (Table 2).

    papA alleles. Eleven papA variants were detected, in order of descending frequency as follows (with the percentage of 329 isolates indicated in parentheses): F10 (15%); F11 (13%); F16 (9%); F14 (8%); F7-1, F7-2, and F48 (5% each); F8 (3%); F9 and F12 (2%); F13 (1.5%). Five alleles (F7-1, F7-2, F10, F14, and F16) were significantly associated with pyelonephritis (Table 1). The only apparent difference between the fecal and cystitis isolates involved the (CGA-associated) F16 allele (17, 19, 30), which was more prevalent among cystitis isolates (12% versus 3%; P = 0.03).

    Virulence scores. Aggregate VF scores were significantly higher among pyelonephritis isolates (median, 9; range, 1 to 14) than among fecal isolates (median, 7; range, 0 to 13) or cystitis isolates (median, 7; range, 1 to 14) (P < 0.001 for both comparisons). Virulence scores did not differ significantly between fecal and cystitis isolates.

    Multivariable analysis. Because of the known associations among VFs, O antigens, and phylogenetic groups (22, 24), stepwise multivariable logistic regression analysis was used to identify bacterial characteristics significantly associated with each source group. First, separate models were constructed to differentiate between the groups in pairwise comparisons (Table 3). In one set of models, the candidate predictor variables included all bacterial traits analyzed, i.e., the 4 phylogenetic groups, the 9 UTI-associated O antigens, the O11/O17/O73/O77 antigens (collectively), and the individual VFs and papA alleles. In these models, at the significance level of a P value of 0.015, 2 variables significantly predicted cystitis (versus fecal), including ibeA (positive) and the K1 kpsM variant (negative). In contrast, six variables significantly predicted pyelonephritis (versus fecal), including papEF (P fimbriae subunits), iha (putative adhesin-siderophore), and ibeA (all positive), and the F8 papA allele, papG allele III (P adhesin variant), and the K1 kpsM variant (all negative). Likewise, 4 variables significantly predicted pyelonephritis (versus cystitis), including papG allele II and the O75 antigen (both positive), and the F16 papA allele and group B1 (both negative). In a similar set of models in which candidate predictor variables were limited to papA alleles and VFs (without phylogenetic groups and O antigens), the same predictors of cystitis or pyelonephritis (versus fecal) emerged. However, newly predicting pyelonephritis (versus cystitis) were afa/draBC (Dr-binding adhesins) and malX (pathogenicity island marker), with no negative predictors (Table 3).

    Next, multivariable models were constructed to differentiate fecal isolates from all urine isolates (i.e., cystitis plus pyelonephritis isolates) and pyelonephritis isolates from all nonpyelonephritis isolates (i.e., fecal plus cystitis isolates), using the same two sets of candidate predictor variables as above (Table 4). Significant predictors of fecal isolates (versus urine isolates) with both sets of candidate predictor variables included iha, papEF, and ibeA (all negative), and K1 (positive). For pyelonephritis isolates (versus all other isolates), with the first (extended) set of candidate predictors, significant predictors included group B2, the O75 antigen, and papG allele II (all positive), and K1 (negative), whereas with the second (restricted) set of candidate predictors, afa/draBC and sfa/focDE replaced O75 and group B2 as positive predictors (Table 4).

    Virulence profiles. To determine whether distinctive combinations of VFs also might differentiate among the three clinical source groups, aggregate VF profiles were analyzed. The 329 isolates exhibited 190 unique VF profiles. Of these profiles, 148 (78%) occurred in a single isolate each (148 isolates total), 31 (16%) occurred in from 2 to 4 isolates each (70 isolates total), and 11 (6%) occurred in 5 isolates each (range, 5 to 22; median, 7; 111 isolates total) (Table 5). Of these 11 frequent profiles, profiles 1 to 7 corresponded with familiar ExPEC clonal groups, including CGA (profiles 1 and 2; differing only for fyuA ), the O1/O2:K1:H7 clonal group (profile 3), the O18:K1:H7 clonal group (profile 4), the O6:K15:H31 clonal group (profile 5), and the O75:K+ clonal group (profiles 6 and 7; differing only for iutA ). These 11 VF profiles were broadly distributed by source group; 5 included pyelonephritis isolates plus either fecal (n = 3) or cystitis isolates (n = 2), whereas 6 included all 3 source groups. Notably, none included fecal and cystitis isolates without pyelonephritis isolates, or a single source group only.

    Nonetheless, 5 of the 11 frequent VF profiles did exhibit some degree of syndrome specificity (Table 5). Two (profiles 1 and 6) were significantly overrepresented among pyelonephritis isolates, and 2 others (profiles 2 and 11) were overrepresented among cystitis isolates, with profile 11 also being significantly underrepresented among pyelonephritis isolates. In contrast, profile 3 was significantly overrepresented among fecal isolates, and profile 9 exhibited a similar trend (P = 0.052). In comparisons limited to fecal and cystitis isolates, profile 2 (P=0.03) and profiles 1 and 2 combined (P = 0.01) were significantly associated with cystitis, whereas profile 3 was significantly associated with fecal isolates (P = 0.03).

    VF profile tree. Cluster analysis of aggregate VF profiles yielded a tree consisting of two major clusters (I and II), each comprising two subclusters (not shown). Isolates were significantly distributed within this tree according to clinical group (Table 6). Within cluster 1 (n = 175), pyelonephritis isolates predominated overwhelmingly, whereas within cluster II (n = 150), the three source groups were evenly distributed. Overall, pyelonephritis isolates exhibited a declining prevalence gradient, from predominance within subcluster Ia to a minority position within subcluster IIb. Fecal isolates exhibited an opposite trend, whereas cystitis isolates exhibited an intermediate pattern of distribution. These prevalence shifts were statistically significant within the two main clusters and within three of the four subclusters (Ia, Ib, and IIb) (Table 6).

    In the VF profile tree, 3 smaller clades were identified that contained 5 isolates each, exclusively from a single source group. All 3 of these clades contained only pyelonephritis isolates. The numbers of isolates per clade (the P value for prevalence of pyelonephritis isolates in clade versus remainder of population is given in parentheses) were as follows: clades 1 and 2, 9 isolates each (P = 0.004); clade 3, 7 isolates (P = 0.015). In clades 2 and 3 (which were closely related), all 16 constituent isolates expressed the O2 antigen and had virulence profiles corresponding with the O2:K5/K7:H1 clonal group (24).

    The fecal and cystitis isolates did not differ significantly according to relative prevalence by major cluster or subcluster (Table 6). Likewise, no clade with 5 members contained only fecal or only cystitis isolates, without representatives of another source group. However, when analyzed apart from the pyelonephritis isolates, fecal and cystitis isolates were significantly more likely to have as their nearest neighbor in the VF tree a representative of the same source group, as opposed to a member of the alternate source group (P = 0.01, McNemar's test).

    As for segregation of urine isolates (i.e., cystitis plus pyelonephritis isolates) from fecal isolates by virulence profiles, 4 clades with 5 members contained only urine isolates, without fecal isolates. The numbers of isolates per clade (the P value for prevalence of urine isolates in the clade versus the remainder of population is given in parentheses) were as follows: clade A, 19 isolates (P = 0.01); clade B, 24 isolates (P = 0.002); clade C, 12 isolates (P = 0.08); clade D, 6 isolates (P > 0.10); and clade D, 7 isolates (P > 0.10). The associated VF profiles were quite extensive (not shown). By VF profile, O antigens, and phylogenetic group, clade B corresponded with CGA and clade C corresponded with the O2:K5/K7:H1 clonal group. In contrast, 3 other clades with 5 members each contained only fecal and cystitis isolates, without pyelonephritis isolates. P values for the prevalence of nonpyelonephritis isolates in these clades, versus the remainder of the population, ranged from 0.01 to 0.03. These clades were smaller and more diverse than the pyelonephritis-associated clades. Each comprised only 5 to 6 isolates (typically with sparse virulence profiles) but multiple O antigens and phylogenetic groups (not shown).

    Bacterial characteristics in relation to colony count. The similarity of the cystitis and fecal isolates suggested the possibility that, in some instances, fecal contaminants were misclassified as cystitis due to the low colony count criterion used for cystitis. Accordingly, bacterial characteristics were analyzed in relation to colony count among the cystitis isolates, with the expectation that low-count isolates (if fecal contaminants) should exhibit a lower prevalence of UTI-associated O antigens, VFs, and phylogenetic group B2 than high-count isolates. However, with three different colony count thresholds used to dichotomously stratify the population, the few significant differences that were detected (0 to 4 per stratification) actually involved a higher prevalence of virulence-associated traits among low-count isolates (not shown).

    Phylogenetic distribution of bacterial traits. The similarity of cystitis and fecal isolates also prompted an assessment of whether bacterial traits were phylogenetically distributed as expected. Indeed, 4 of the UTI-associated O antigens were significantly concentrated within group B2, and the O7 and (CGA-associated) O11/O17/O73/O77 antigens were concentrated within group D (Table 7). Likewise, 4 papA alleles were significantly associated with group B2, and the F16 allele was associated with group D (Table 7). Similarly, 23 VFs were significantly phylogenetically distributed, with group B2 exhibiting the highest prevalence for all VFs but papG allele II, iha, and iutA, which instead were significantly concentrated within group D (Table 8). Accordingly, aggregate VF scores (medians and ranges are given in parentheses) were highest within group B2 (9; 2 to 14), intermediate within group D (7; 0 to 12), and lowest within groups A (2; 1 to 11) and B1 (2; 0 to 10) (P < 0.001 for each group versus all others).

    DISCUSSION

    We found that among E. coli isolates from U.S. women, acute pyelonephritis isolates differed greatly from contemporaneous cystitis and fecal isolates according to phylogenetic group, O antigens, and VFs, whereas cystitis and fecal isolates exhibited considerably fewer (and subtler) differences. Additionally, although certain virulence profiles and groups of related profiles were significantly distributed by source group, no one VF or profile was confined to a single source group. These findings identify potential targets for anti-UTI vaccines, suggest that UTI pathogenesis is multiply determined, and indicate that most ExPEC clonal groups and their distinctive VFs may be syndromically versatile.

    Not surprisingly, pyelonephritis isolates exhibited a much greater prevalence of phylogenetic group B2, UTI-associated O antigens, and individual VFs, plus higher aggregate VF scores, than did cystitis and fecal isolates. They also accounted for several prominent clades within the VF profile tree, two of which corresponded with familiar ExPEC clonal groups, specifically E. coli O2:K5/K7:H1 and O75:K+ (24), thereby identifying these as "pyelonephritogenic clones" (35). Notably, the individual VFs that, in various multivariable models, were significant predictors of pyelonephritis included three traditionally recognized "uropathogenic" traits (papG allele II, afa/dra, and sfa/foc), plus a more recently identified meningitis-associated trait (ibeA) (10) and two relative newcomers, iha and malX (21, 24). Experimental data indicate that papG II, afa/dra, sfa/foc, and iha contribute to the pathogenesis of pyelonephritis (8, 14, 31, 38). Likewise, malX, heretofore regarded only as a pathogenicity island marker, was recently shown to contribute to experimental avian septicemia (29). Experimental assessment of malX and ibeA as uro-VFs is warranted, since these may be useful targets for interventions such as vaccines.

    In contrast, the cystitis isolates differed surprisingly little from the fecal isolates. Only two individual VFs differentiated these groups, and the differences were in opposing directions, resulting in similar aggregate VF scores. Between-group differences in virulence profiles were also subtle. However, statistically significant clustering of virulence profiles by source group (cystitis versus fecal) was found, both by prevalence assessments involving individual profiles or groups of related profiles and by "nearest neighbor" analysis. Likewise, in the multivariable analyses, the fecal and cystitis isolates exhibited nonoverlapping sets of predictor variables that differentiated either group from pyelonephritis isolates. Thus, the cystitis and fecal isolates differed statistically but in ways not obviously suggesting greater virulence for the cystitis isolates or identifying useful targets for interventions. One exception was the significant association with cystitis (versus fecal) of E. coli CGA. This provided novel epidemiological evidence of enhanced urovirulence for this recently emerged multidrug-resistant clonal group and suggested that interventions against it could be protective (17, 19, 30).

    Several possible explanations for the considerable similarity of cystitis and fecal isolates were considered. Misclassification bias seemed unlikely, since low-count cystitis isolates appeared as virulent as or more virulent than high-count isolates. The phylogenetic distribution of VFs, VF scores, and O antigens within the total population was consistent with previous work, evidence against laboratory artifacts, or anomalies within the collection. Significant host mismatching between the fecal and cystitis subjects also seemed unlikely, since these isolates were collected approximately concurrently from women eligible to attend the same university student health service. Future analysis of host characteristics in relation to bacterial traits within the cystitis and fecal groups might be informative (18, 23), as might comparisons of unique fecal and urine clones from subjects with cystitis (22). It is probable that the fecal group included a number of potential cystitis isolates that were residing innocuously within the fecal reservoir (47), the presence of which would tend to bias comparisons toward the null. Finally, our presence-absence testing may have overlooked key determinants of cystitis, possibly including unrecognized VFs (49), minor sequence variants of known VFs (45), or differences in VF expression (9).

    Interestingly, whereas by molecular criteria the present cystitis isolates appear to be generally as virulent as previously analyzed cystitis isolates, the present fecal isolates appear more virulent than other reported fecal isolates (4, 16, 20, 22, 28, 32, 39, 44, 50). Since fecal E. coli populations can vary by locale and host group (4, 44, 50), it may be that the present control subjects have a comparatively high-virulence colonic flora. If so, and if colonization with virulent E. coli is a rate-limiting step in the development of UTI (47), it may be that the incidence of UTI is higher in the present control population than in similar populations with a less-virulent fecal flora. Future comparative studies of UTI incidence in relation to the molecular virulence characteristics of the local fecal E. coli population would be of interest.

    Our findings suggest that no single VF or virulence profile and few groups of related profiles are entirely specific to cystitis, pyelonephritis, or UTI in general. Although statistically significant differences were detected, most were relative, not categorical. Conversely, VF profiles were quite diverse within each source group, and multiple VFs contributed significantly in combination to statistical differentiation among source groups. These observations argue against a strict linkage of specific VFs or VF profiles (and the corresponding clonal groups) with a particular clinical source and against the concept that a single VF underlies extraintestinal virulence. Accordingly, optimal anti-VF interventions may need to address multiple targets (33); this may provide the added benefit of protection against multiple clinical syndromes (13, 26).

    Limitations of the study include the modest numbers of fecal and cystitis isolates, paucity of clinical/epidemiological data, lack of attention to gene expression and minor sequence variants, and use of multiple comparisons, resulting in an increased risk for type I error. Since this was an exploratory, hypothesis-generating study involving multiple comparisons, the putatively significant associations require validation in future studies before being considered definitive. (Notably, however, many of the observed associations were extremely strong and, hence, are quite unlikely to represent chance findings.) The necessary use of stepwise regression modeling techniques to isolate important predictor variables may have led to a further capitalization on chance variation at the expense of true underlying effects, although to guard against this in these analyses we used a more stringent criterion for statistical significance. In principle, it would be preferable to study pyelonephritis isolates from the same locale as the comparison cystitis and fecal isolates; however, this was logistically unfeasible. Moreover, we are unaware of evidence that the E. coli clonal groups that cause acute uncomplicated pyelonephritis are differentially distributed across the United States in a way that would bias these comparisons.

    The strengths of the study include the large number of clinically well defined, prospectively collected pyelonephritis isolates, inclusion of (prospectively collected) fecal isolates from the same locale and similar time frame as the (prospectively collected) cystitis isolates, the extensive array of traits assessed, which have been shown to predict experimental virulence (15, 37), and the use of multiple complementary analytical approaches.

    In summary, we found that E. coli isolates from women with acute pyelonephritis differed considerably from contemporaneous cystitis and fecal isolates, which in contrast differed minimally. Although certain virulence profiles were significantly distributed by source group, no single VF or profile was confined to a single source group. E. coli CGA was prominent in both cystitis and pyelonephritis, whereas the O2:K5/K7:H1 and O75:K+ clonal groups were particularly prominent in pyelonephritis. These findings identify potential vaccine targets, suggest that urovirulence is multiply determined, and indicate that many ExPEC clonal groups and VFs may be pathogenically versatile.

    ACKNOWLEDGMENTS

    This material is based upon work supported by the Office of Research and Development, Medical Research Service, Department of Veterans Affairs.

    Timothy T. O'Bryan (Veterans Affairs Medical Center; current affiliation, Gentra Systems, Minneapolis, MN) provided expert technical assistance, and Ann Emery (Veterans Affairs Medical Center) helped prepare the manuscript.

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作者: James R. Johnson, Krista Owens, Abby Gajewski, and 2007-5-10
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