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W2012083610 abstract "INTRODUCTION The gastrointestinal tract of a healthy fetus is sterile. In full term infants, the bacterial colonization of the gastrointestinal tract has been extensively studied if not entirely understood. During the birth process and rapidly thereafter, microbes from the mother and the surrounding environment colonize the gastrointestinal tract until a dense and complex bacterial community is established. In vaginally delivered neonates, bacteria appear in the stools during the first day of life, with usually Escherichia coli and Enterococcus spp., among the first, followed within the first 5 days by Bifidobacterium spp. Because, at this stage, the composition of the gut bacterial community is strongly influenced by the diet, a shift in the bacterial composition can be observed. By 10 days of age, most healthy full term neonates are colonized with a heterogeneous bacterial flora, with bifidobacteria dominant in breast-fed infants and a more diversified flora in formula-fed infants (1). A dynamic balance exists between the bacterial community, the host physiology, and the diet: all of them influence initial acquisition, subsequent development and eventual stability of the gut ecosystem (2). In contrast, in preterm infants, especially extremely low birth weight preterm infants (weighting less than 1,000 g at birth), bacterial colonization and its consequences on health have not been extensively studied. Many factors influence the biodiversity of the intestinal flora and may increase the risk of gastrointestinal disease such as necrotizing enterocolitis (NEC): immaturity of the main vital functions, the characteristics of the medical environment, from delivery to hospital discharge, the developmental stage of gastrointestinal and immune functions, the mode and environment of delivery, the feeding regimen, the kind of drug therapy (such as antibiotics, corticoids, etc.), or of other therapy (such as oxygenation). In adults, the human cecal flora differs quantitatively and qualitatively from the fecal flora. Facultative anaerobes represented 25% of total bacteria in the cecum versus 1% in the feces (3). So, the biodiversity of the bacterial community should be studied at these different levels of the gastrointestinal tract. For obvious reasons, most of the studies were performed on stool samples. In recent years, the use of ribosomal RNA, in particular, sequences of the 16S rRNA genes, has greatly facilitated the study of gastrointestinal tract ecology because it allows a culture-independent analysis of the fecal microbial community. In adult fecal samples, molecular tools have indicated that 60% to 80% of the total human microflora has not been cultivated (4). Techniques such as polymerase chain reaction, gene sequencing, in situ hybridization, and denaturing gradient gel electrophoresis are routinely used to study gut microbial ecology and have been recently reviewed by Suau (5). So far, only three studies inspected the microbial composition of premature infants using molecular methods (6-8). Thus, the aim of the present review is to describe the composition of fecal microbial community in preterm infants from the colonization of sterile gut, to present the different factors that contribute to its alterations, and to link the gut microflora to diseases such as NEC. This review is essentially based on data collected using traditional bacterial culture from fecal samples. BACTERIAL COLONIZATION IN PRETERM INFANTS In contrast with full term neonates, little information concerning the composition of the bacterial community in premature infants is available at the moment. Succession of bacterial populations in the large bowel of preterm infants differs from full term neonates (9). At birth, the gut is sterile. Furthermore, first or second meconium was sterile in seven preterm infants tested (10). Gastrointestinal tracts of preterm infants are colonized by less than three bacterial species by the 10th day of life, as opposed to a more complex and diverse colonization pattern observed in healthy, full term neonates (11). Compared with full term infants, the denaturing gradient gel electrophoresis patterns in preterm infants, which represent the dominant species present, were very simple at birth, and diversity increased over time (8,12). Similarity of band patterns showed that preterm infants acquired a diverse bacterial community after birth but, as a result of hospitalization, tended to develop a similar strain composition over time (8). The ratio of gram negative to gram positive species increased with time from 0.36:1 at day 10 to 0.87:1 at day 30 (11). With time, the total number of different species per specimen significantly increased (11). Neither gestational age nor birth weight were correlated with the number of fecal bacterial species (day 10 or day 30) (11). Facultative Anaerobic Bacteria At the first day of life, the preterm infants were predominantly colonized by facultative anaerobic bacteria (13), which remained at high levels, resembling the full term formula-fed infants (9). During this period, enterobacteria and enterococci appear in stools at the same levels as full term formula-fed infants, reaching, respectively, 5 × 108 and 2 × 106 organisms per gram of feces (wet weight) (9). Similarly, in another study, the same levels were observed between preterm infants and full term formula-fed infants, and counts of enterobacteria and enterococci in preterm infants were, respectively, 6.3 × 108 and 5 × 108 organisms per gram of feces (wet weight) (10). From day 3, counts of enterobacteria in preterm infants, reaching 2 × 109 organisms per gram of feces (wet weight), were significantly higher than in full term breast-fed infants but similar to counts in full term formula-fed infants (9). In contrast with full term neonates, enterobacteria and enterococci remained predominant until the 20th day of life (9,10), reaching, respectively, 3 × 109 and 8 × 108 organisms per gram of feces (wet weight) (10). From 2 to 4 weeks, counts of enterococci in preterm infants were again significantly higher than in full term breast-fed infants although lower than full term formula-fed infants. Counts of enterococci were 2.5 × 108 organisms per gram of feces (wet weight) in preterm infants, 1.5 × 106 organisms per gram of feces (wet weight) in full term breast-fed infants, and 5 × 109 organisms per gram of feces (wet weight) in full term formula-fed infants (9). E. coli was the most frequent facultative anaerobic species isolated from fecal samples during the first week (13-15). Enterococcus faecalis was also commonly isolated (13). Another study frequently observed E. coli and Klebsiella spp., and both persisted after day 4 (14). In addition, Klebsiella spp. on the first day could be detected at a low level (17%) within the flora, but approximately 59% of the babies were colonized on day 6 (13). Rotimi et al. (13) also observed a mixed population of E. coli and E. faecalis, with few anaerobes becoming rapidly predominant by the end of the first week. Thus, anaerobes became qualitatively and quantitatively (growth density) more frequent in the feces than aerobes. Bifidobacteria In contrast with full term infants, bifidobacteria did not appear during the first days of life. This colonization delay was more important in comparison with breast-fed full term infants, but these organisms seemed to appear even later than in full term formula-fed infants (9). Bifidobacterium genus was the most frequent anaerobic genus isolated. Approximately 95% of the preterm infants were colonized by the end of the first week of life (13). Bifidobacteria could also be detected in half of the infants studied on day 8 (9,10) and were retrieved in all infants from day 14 (10). Although they became predominant between day 12 and 35 with approximately 3.2 × 1010 organisms per gram of feces (wet weight), their predominance was not as strong as in full term infants (10). The ratio of bifidobacteria to enterobacteria was approximately 10 to 1 compared with 1,000 to 1 in full term breast-fed infants (10). In contrast, bifidobacteria from preterm infants were rarely identified in the first month of life in the study of Gewolb et al. (11). Sakata et al. (10) suggested that the delay in bifidobacterial colonization could be related to the low milk intake of preterm infants. Bacteroides spp. As evidenced by two studies, within the first week, preterm infants were rapidly colonized by Bacteroides spp. (9,14). This high rate of Bacteroides colonization agrees with the study of Rotimi et al. (13) in which 80% of the babies studied were colonized by Bacteroides spp. by day 6. The major species isolated were B. vulgatus and B. thetaiotaomicron; B. ovatus and B. distasonis were also isolated (13). Counts of Bacteroides spp. were 3 × 1010 organisms per gram of feces (wet weight) (10). Unlike their transient appearance in full term breast-fed infants, they persisted after the first week (9). In contrast, the study of Sakata et al. (10) suggested that emergence of Bacteroides spp. was delayed beyond 10 days compared with full term infants, and their isolation rates were low. Finally, in another study, they were rarely isolated during the whole first month (11). Clostridia Clostridium spp. were rarely isolated and appeared in feces in small numbers soon after birth (14,16). In the study of Sakata et al. (10), Clostridium spp. were detected only at day 11, and reached 106 organisms per gram of feces (wet weight). In another study, they were also observed during the first week in half of the preterm infants studied (9). In a study, Clostridium spp. were isolated with a low frequency during the first 16 days of life and more frequently after (14). In contrary, Rotimi et al. (13) found a high rate of clostridial colonization and their frequency increased daily during the first 6 days of life. C. butyricum and C. perfringens were more common than C. difficile, which was rarely detected (13,14). This finding was not confirmed thereafter (16). Staphylococcus spp. Staphylococci were isolated immediately after birth from most infants (10,11,13,15,16). The most retrieved species were S. epidermidis (11,13-15), S. aureus (11,13,14), and S. haemolyticus (11). The number of viable staphylococci in stools of preterm infants was generally higher than in full term infants: at day 7, approximate counts were 107 per gram of feces (wet weight) for preterm infants and 2.5 × 104 per gram of feces (wet weight) for full term infants, and they gradually decreased over 7 weeks of life (10). Lactobacilli Lactobacilli counts were very different among several studies in preterm infants. Lactobacilli were seldom isolated. Within the first week, lactobacilli were not detected (10) or their detection frequency was less than 14% (11,13,14,17); their counts represented 5.2 × 107 organisms per gram of feces (wet weight) (17). Conversely, Boehm et al. (18) detected lactobacilli in all preterm infants at the end of the first week. At day 30, lactobacilli were still rarely detected in two studies (11,13). But in two others, they were more frequent and were found in 25% (14) and 19% (17) of the preterm infants studied. At day 30, counts of lactobacilli were similar in comparison with the first week: 1.5 × 107 (17) and 2 × 107 (10) organisms per gram of feces (wet weight). Other Genera Other organisms have occasionally been cultured: Pseudomonas spp. (10,13) such as P. aeruginosa (11), Enterobacter spp. (11,14) such as E. cloacae and E. aerogenes (11), Proteus spp. (13,14), Veillonella spp. (10,11), Citrobacter spp. (11), Corynebacterium spp. (11), Serratia spp. (11), Eikonella spp. (11), Propionobacterium spp. (11), Eubacterium spp. (13), and Neisseria spp. (13). INFLUENCE OF DELIVERY For the colonization of infants born by caesarean section, the environment is extremely important: in full term infants, gut flora may be disturbed for up to 6 months after birth (19). In contrast, many studies of the fecal flora of preterm infants did not demonstrate any differences between the two types of delivery (10,11,17). Conversely, a study demonstrated an influence of the delivery method during the first 3 days (13). No significant difference has been observed in the isolation rates of enterobacteria and enterococci; nevertheless, there was a general delay in the colonization of the babies delivered by caesarean section by Bacteroides and clostridia (13). INFLUENCE OF FEEDING In full term infants, one major difference between breast-fed and formula-fed infants is the development of the intestinal flora (20). In particular, human milk may promote growth of bifidobacteria in the intestine (1). In preterm infants, colonization patterns were similar in both breast-milk-fed and formula-fed infants (11,17). Nevertheless, there are some differences: breast-milk-fed preterm infants initially had a higher incidence of K. pneumoniae colonization; conversely, incidence of colonization with S. haemolyticus was higher in formula-fed preterm infants on day 30 but not before that (11). Breast milk preterm infants had a more diverse, but not necessarily larger, bacterial population than did their formula-fed counterparts (11). Thus, preterm infants fed their own mother's frozen breast milk demonstrated also a significant increase in colonization by aerobes (78% vs. 46%) as well as a more frequent isolation of S. epidermidis (15). In addition, frozen human milk may be a vehicle for gastrointestinal S. epidermidis colonization (15). The method of feeding also influences flora acquisition: in the study of Blakey et al. (14), parenteral feeding during the first 4 days of life was associated with a delayed colonization and with a restricted bacterial diversity. ANTIBIOTICS In preterm infants, the duration of antibiotic treatments in the first month of life was correlated with a decrease in the bacterial diversity and the total number of organisms in stool samples at day 30 (11). In a study, preterm infants, treated with amoxicillin and netilmicin were colonized by high levels of K. oxytoca and by amoxicillin resistant E. coli but at lower levels than usual (21). Intravenous antibiotic regimens such as benzylpenicillin, cloxacillin, flucloxacillin, ampicillin, cefuroxime, cefoxitin, and gentamicin led to a decrease of anaerobic bacteria and an overgrowth of Klebsiella spp. but not with other gram negative bacteria (16). Furthermore, in this study, a slight colonization with C. difficile and C. perfringens occurred compared with a control group (16). In the fecal flora of preterm infants receiving either penicillin or penicillin and gentamicin during the first 4 days of life, the incidence of Clostridium spp. was reduced, and Lactobacillus spp. were never isolated until 20 days of age compared with those who did not receive antibiotics (14). In preterm infants treated with three intravenous antibiotics (amoxicillin, netilmicin, and cefotaxime), staphylococci colonization occurred rapidly; furthermore, their levels remained higher than usual. Such proliferation appeared to be enhanced by a defective colonization with facultative anaerobic bacteria under the effect of cefotaxime (21). NECROTIZING ENTEROCOLITIS NEC is a severe gastrointestinal disorder in newborns, affecting predominantly premature or low birth weight infants. Most of the newborns affected are premature infants (62-94%). This disease is characterized by gastrointestinal dysfunction progressing to pneumatosis intestinalis, pneumoperitoneum, systemic shock, and rapid death in severe cases. Despite its significant impact on preterm infant morbidity, the exact etiology and pathogenesis of this disease could not be clearly delineated. Prematurity or low birth weight are the most reported associated factors. The mean age at disease onset was 9.5 (range 6.6-29) days (22). NEC infants were statistically significantly more often preterm and had lower birth weights than the controls (23). Period of NEC occurrence was inversely correlated with gestational age at birth (24). Breast milk has been reported to protect against NEC (25). In exclusively formula-fed preterm infants, confirmed disease was 6 to10 times more common than in those only breast milk fed and 3 times more common than in those who received formula and breast milk (26). Similarly, among infants with NEC in another study, a majority was exclusively formula fed (24). Initiation of breast milk feeding occurred statistically later in the NEC group than in the control groups (23). Nevertheless, optimal enteral feeding methods in preterm infants have not been well defined. Controversy exists regarding when feeding should be started, whether minimal enteral feeding should be used routinely in small preterm infants, and how fast to advance enteral feeding. Previous prospective studies have shown that infants given small enteral feeding (2-24 mL/kg per day) for the first 7 to 10 days of feeding do not have an increased risk for NEC compared with those given no feeding. A recent study by Berserth et al. (27) analyzed feeding modes of infants of less than 32 week's gestation: 20 mL/kg per day for 10 days and an advancing feeding volume, starting at 20 mL/kg per day and increasing daily by 20 mL/kg per day until a volume of 150 mL. The trial was prematurely stopped because the data safety committee found an increased risk of NEC in infants who were advanced daily (10%) compared with those who had minimal enteral feeding (1.4%) (27). Moreover, several retrospective studies have suggested that advancing feedings rapidly was associated with an increased risk of NEC (28,29). Observations of an apparent clustering of cases led to the hypothesis that NEC is causally related to specific infectious agents (24) such as C. perfringens (6). Nevertheless, no single organism was proved to be responsible for disease, and most of the micro-organisms identified are present in the normal gut flora (7), but various “pathogens” can cause NEC in a sufficiently vulnerable hosts (24). Only one study described quantitative changes in fecal microflora during the weeks preceding episodes of neonatal NEC involving E. coli, K. pneumoniae, and E. cloacae (30). A decrease in the number and diversity of aerobic and anaerobic bacteria was observed. Furthermore, increasing amounts of enterobacteria during 72 hours preceding onset of NEC were found (30). These described changes may result from changes in intraluminal conditions before the clinical onset of NEC (substrate availability and pH) (30). All enterobacteria ferment glucose with the formation of acid and hydrogen gas, and intestinal fermentation has been suggested as a possible pathogenesis of NEC (31). In vitro adherence to Caco2 cells of E. coli isolated from NEC patients and subsequent reproduction of disease in weaning rabbits could be blocked by co-infection with enterococci or staphylococci isolated from control children. In contrast, adherent E. coli from NEC cases retained their adherence and caused illness in rabbits when co-infected with gram positive isolates from the homologous child. These results suggested that patterns of intestinal adherence, influenced by the underlying intestinal microbial ecology, played a role in the pathophysiology of NEC (32). Moreover, the oral administration of L. acidophilus and B. infantis associated with breast milk reduced the incidence of NEC in preterm infants aged of 1 week. The incidence of death or NEC (≥stage 2) was significantly lower in the study group compared with the control group (2 of 180 vs. 10 of 187) (33). In contrast, in another study, no significant differences between probiotics (L. acidophilus and B. infantis) and placebo group were observed in regard to incidence of NEC (34). However, the rate was low in the control group for NEC (1.4%), which needed a much larger sample size to verify the hypothesis (33). The main common risk factors reported are prematurity, enteral feeding, and bacterial colonization. Claud and Walker (35) suggested that the intestinal injury in NEC may be a result of the synergy of these three risk factors in which feeding resulted in colonization of susceptible, premature intestine with bacteria leading to an exaggerated inflammatory response. PROBIOTIC A probiotic can be defined as “a live microbial” feed supplement, which beneficially affects the host animal by improving its intestinal balance (36). However, the scientific basis of this definition has recently been questioned because animal studies suggest that some probiotic effects can be achieved by nonviable bacteria and even by bacterial DNA (37,38). Therefore, probiotics have more recently been defined as “microbial cell preparations or components of microbial cells with a beneficial effect on the health and well being the host” (39). It has been suggested that induced colonization of preterm infants with a probiotic strain may produce bacteriologic, metabolic, and clinical benefits for them. Probiotic supplementation in preterm formula-fed infants showed that some strains can persist in the infant gut. To date, many strains have been investigated to determine whether they can colonize the immature bowel of preterm infants. The only aerobe studied was E. coli (40), whereas anaerobes classified as lactic acid bacteria such as Bifidobacterium breve (41,42), Lactobacillus acidophilus (43), and Lactobacillus GG (44,45) were also studied. Two nonpathogenic and antibiotic-susceptible E. coli strains administered to premature infants were able to colonize the digestive tract and to reach high population sizes in the feces (≥107 organisms per gram of feces, wet weight). They also significantly reduced the colonization by antibiotic resistant enteropathogens through antagonistic abilities. Consequently, it appeared that the use of E. coli strains could be proposed as a practical measure aimed at protecting preterm infants (40). Bifidobacterium breve was the most frequent species of Bifidobacterium in full term breast-fed infants. This species was detected in 70% of full term breast-fed infants tested (46). B. breve was administrated to preterm infants and was able to colonize very efficiently the intestine (41,42). The initial day of Bifidobacterium detection in preterm infants who received B. breve several hours after birth was significantly earlier (3.4 ± 2.2 days) than preterm infants who received B. breve 24 hours after birth (7.2 ± 3.8 days) (42). In the study of Li et al. (42), in preterm infants who received the B. breve several hours after birth, the number of Enterobacteria at 2 weeks was significantly lower (3.2 × 108 organisms per gram of feces, wet weight), than for the preterm infants who received B. breve 24 hours after birth (1010 organisms per gram of feces, wet weight). Conversely, in an other study, B. breve administration did not change bacterial counts within fecal flora but was associated with fewer abdominal abnormal signs and a better weight gain in preterm infants (41). There was no evidence that the administration of Lactobacillus acidophilus had any positive clinical benefit on a group of premature infants, nor on bowel colonization with enterobacteria (43). Similarly, no qualitative or quantitative differences was found in fecal flora of preterm infants fed with Lactobacillus GG supplementation (strain of Lactobacillus casei) (44). A limit of this study was that colonization with Lactobacillus GG occurred only in infants who did not receive antibiotics. Although resistant to certain antibiotic such as vancomycin (because of the presence of an atypical peptidoglycan cell wall), Lactobacillus strains are sensitive to a variety of commonly used antibiotics. Millar et al. (44) suggested that intravenous flucloxacilin and netilimicin may have a profound influence on bowel colonization by Lactobacillus GG. In vitro, the pattern of antibiotic sensitivity of Lactobacillus GG reveals sensitivity to a broad spectrum of antibiotics such as ampicillin, gentamicin, amikacin, kanamicin, ciprofloxacin, augmentin, netilmicin, ceftazidime, and penicillin (45). Most preterm infants receive prophylaxis antibiotics. In consequence, colonization by Lactobacillus GG may be difficult and require prolonged therapy beyond the period of antibiotic use. To sum up, if potential probiotic bacteria disappear in the intestine as a consequence of an additive therapy (e.g., antibiotics), there is no reason to expect a probiotic effect. PREBIOTICS Prebiotics are defined as nondigestible food ingredients that beneficially affect the host by selectively stimulating the growth or activity of one or a limited number of species in the colon (47). Prebiotics are not much studied in preterm infants. At this time, all prebiotics used in preterm infants are oligosaccharides. Human breast milk has many specific and nonspecific components thought to protect against potentially pathogenic bacteria. Among them, the oligosaccharide fraction is considered to be beneficial in infants (48). Furthermore, there is some evidence that free oligosaccharides are potent inhibitors of bacterial adhesion, which is an initial stage of infection, by acting as cell receptor analogues (49). Oligofructose is known to stimulate the growth of bifidobacteria in adults (50). A prebiotic oligosaccharide mixture can significantly stimulate bifidobacterial growth (18). The first effect of the supplementation was observed after 14 days and was more pronounced after 28 days. In this study, bifidobacteria were detectable on the first measurement day in fecal samples of all preterm infants before supplementation (18). Similarly, in a model of quails, oligosaccharide significantly increased the level of bifidobacteria in association with a decrease of E. coli or of C. perfringens and C. ramosum. However, C. difficile was unaffected by this bifidobacterial increase (48). Quails with preterm infant flora in absence of bifidobacteria were used as a model of NEC (51). Using this model, Butel et al. (52) showed that the bifidogenic effect of oligofructose is dependent on the initial level of bifidobacteria in the intestinal microflora. In addition, the regular ingestion of oligofructose did not entail bifidobacterial colonization when bifidobacteria were initially absent. Nevertheless, oligofructose could act as an anti-infective agent and decrease the occurrence or severity of the lesions depending on the bacteria involved (52). Probiotics need to be administered regularly to persist in the bowel of preterm infants. Oligofructose contributed to bifidobacterial colonization at a high level after a single early administration and reduced colonization by potentially pathogenic bacteria (48). Therefore, the addition of oligofructose in formula milks may be a nutritional approach to favor colonization by a beneficial flora (52). CONCLUSION At the present time, it is difficult to draw firm conclusions on the fecal microbial community in preterm infants for two main reasons: (1) the interindividual variability is very high, both in terms of composition and counts, and (2) so far, the methodological approach has been far from optimal: many parameters that cannot easily be controlled such as environment of hospital, antibiotic regimens, and diet may tend to increase the study discrepancy (Table 1). The limited number of preterm infants analyzed did not allow us to fully understand the intestinal bacterial colonization. In addition, cultural methods used in most studies are time consuming and involve fresh samples, thus restricting the number of subjects. Thus, in principle, molecular techniques can lead to an in-depth knowledge of intestinal colonization in preterm infants.TABLE 1: Detection of bacterial groups using culture in the fecal samples of preterm infantsWe can tentatively conclude that (1) the number of species is low, with typically only three bacterial species found at 10 days of age, (2) three groups including enterobacteria such as E. coli and Klebsiella spp., enterococci such as E. faecalis, and staphylococci such as S. epidermidis, S. aureus, and S. haemolyticus are the most frequently retrieved, (3) all these facultative anaerobes persist at high levels in the fecal flora of preterm infants, and (4) in comparison with full term infants, establishment of anaerobes, especially bifidobacteria, is delayed. Nevertheless, lactobacilli and Bacteroides frequencies are study dependent, and no specific pattern can be established. According to what is presently know in preterm infants, the overall results suggest an absence of dynamic balance or interaction between bacterial community and the preterm host physiology. It remains to be seen whether the diet could help in controlling such an interaction." @default.
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W2012083610 title "Fecal Microbial Community in Preterm Infants" @default.
W2012083610 cites W1832474145 @default.
W2012083610 cites W1893993890 @default.
W2012083610 cites W1924732114 @default.
W2012083610 cites W1963588808 @default.
W2012083610 cites W1964351185 @default.
W2012083610 cites W1964377839 @default.
W2012083610 cites W1966509997 @default.
W2012083610 cites W1966919146 @default.
W2012083610 cites W1968088790 @default.
W2012083610 cites W1968593367 @default.
W2012083610 cites W1972857503 @default.
W2012083610 cites W1980210906 @default.
W2012083610 cites W1988086261 @default.
W2012083610 cites W1993314377 @default.
W2012083610 cites W1994340698 @default.
W2012083610 cites W2002854395 @default.
W2012083610 cites W2003360896 @default.
W2012083610 cites W2038483905 @default.
W2012083610 cites W2041559519 @default.
W2012083610 cites W2046802568 @default.
W2012083610 cites W2047575777 @default.
W2012083610 cites W2049645500 @default.
W2012083610 cites W2058404734 @default.
W2012083610 cites W2060776197 @default.
W2012083610 cites W2065992586 @default.
W2012083610 cites W2078170081 @default.
W2012083610 cites W2080689149 @default.
W2012083610 cites W2082917000 @default.
W2012083610 cites W2086077763 @default.
W2012083610 cites W2090210288 @default.
W2012083610 cites W2092669321 @default.
W2012083610 cites W2098557460 @default.
W2012083610 cites W2106608380 @default.
W2012083610 cites W2107307462 @default.
W2012083610 cites W2107853514 @default.
W2012083610 cites W2108581239 @default.
W2012083610 cites W2110706037 @default.
W2012083610 cites W2112751868 @default.
W2012083610 cites W2114811866 @default.
W2012083610 cites W2117130914 @default.
W2012083610 cites W2125200552 @default.
W2012083610 cites W2130890583 @default.
W2012083610 cites W2136734369 @default.
W2012083610 cites W2138253380 @default.
W2012083610 cites W2141953075 @default.
W2012083610 cites W2144826002 @default.
W2012083610 cites W2148606321 @default.
W2012083610 cites W2324228309 @default.
W2012083610 cites W4248567429 @default.
W2012083610 cites W4292994528 @default.
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