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Cancer seed and soil can be highly selective: human-patient colon tumor lung metastasis grows in nude mouse lung but not colon or subcutis.

The question remains as to whether metastatic cells (cancer seed) that eventually colonize a particular organ (cancer soil) have specific properties that distinguish them from the other cells of the primary tumor. However until recently there have not been model systems in which this question could be fully answered. To further understand the relationship between seed and soil we have developed an orthotopic-transplantation nude-mouse model that allows human tumors to essentially replicate their behavior they had in the patient. The patient-like behavior of the transplanted human tumor in the nude mouse depends on the use of intact tumor tissue for orthotopic transplantation. Here we report that a colorectal tumor lung metastasis surgically resected from a patient could grow in nude mouse lung, but not in either the colon or the subcutis after transplantation of intact tissue. The results were striking in that the human colorectal tumor lung metastasis grew in the lung of the animals and not in the colon or in the subcutis of the animals. The results described here suggest that the lung metastasis of the patient colon tumor is distinct in its soil requirement from the majority of the cells of the original colon tumor. In contract, in the intact-tissue orthotopic transplant model, primary human colon tumors grow when transplanted to the colon of the nude mouse. Thus the colorectal cancer "seed" which metastasized to the lung in the patients seems very selective for the "soil" of the lung of both the patient and the nude mouse.

Animals↗

Prevalence of distal colonic neoplasia associated with proximal colon cancers.

BACKGROUND: The number, size, and histologic features of distal colorectal adenomatous polyps have been reported to correlate with the risk of developing proximal colon cancer. To investigate this putative relationship further, we evaluated the frequency of distal colorectal neoplastic polyps in patients with colon cancer located proximal to the splenic flexure. METHODS: All cases of colorectal adenocarcinomas treated at a tertiary referral center and Veterans Affairs hospital between 1979 and 1992 were identified by International Classification of Diseases coding and review of pathology and colonoscopy reports. The medical records of patients with documented cancers proximal to the splenic flexure were examined for the presence, location, size, and histopathologic features of synchronous neoplastic lesions found at colonoscopy. RESULTS: Among 634 patients with colorectal cancer identifiable by location, 172 had proximally located tumors. Of these, 60 patients were excluded because of lack of complete colonoscopy or because surgical resection was performed elsewhere. Forty percent of the remaining 112 patients for whom data could be evaluated demonstrated neoplastic lesions in addition to the proximal cancer. The colon was devoid of "sentinel" neoplasia distal to the splenic flexure and descending colon-sigmoid colon junction in 69% and 72% of patients, respectively. CONCLUSIONS: The majority of proximal colon cancers are not associated with distal sentinel lesions. We surmise that flexible sigmoidoscopy will fail to find evidence of neoplasia in at least 25% of patients with prevalent colon cancers.

Adult↗

The "institutional colon": a frequent colonic dysmotility in psychiatric and neurologic disease.

OBJECTIVES: The true existence of a disease entity termed "institutional colon" has remained controversial. The present study serves to test whether this entity actually exists and how frequently psychiatric and neurologic diseases are associated with colonic dysmotility. METHODS: Using the hospital discharge records of four million US military veterans, we investigated the comorbid occurrence of volvulus, impaction of intestine, constipation, and megacolon with any neurologic or psychiatric disease. RESULTS: Comorbidity of colonic and neurologic/psychiatric diseases in identical subjects occurred two to three times more often than one would expect from the overall distribution of each group of diseases alone. Presenile dementia and Alzheimer's disease, Parkinson's disease, multiple sclerosis, and quadriplegia were associated significantly with all four colonic diseases. The various forms of schizophrenia coincided mostly with megacolon and constipation. Major depressive disorder was associated only with constipation, but with none of the other colonic diseases. CONCLUSION: Psychiatric and neurologic diseases are frequently associated with colonic dysmotility. The association raises the possibility of a pathophysiologic link involving the neuronal control of colonic motility.

Colonic Diseases↗

A comparative study of hepatic and colonic metabolic enzymes in inbred mouse lines before and after treatment with the colon carcinogen, 1,2-dimethylhydrazine.

1,2-Dimethylhydrazine (DMH) is an organotropic colon carcinogen that undergoes metabolic activation to DNA-reactive metabolites. Twenty hours after parenteral treatment of AKR/J (colon tumor resistant) and SWR/J (susceptible) mice with DMH.2HCl (70 mg/kg), functional levels of Cyp1a1 and Cyp2e1 were examined by measuring O-deethylation of ethoxyresorufin (EROD) and hydroxylation of p-nitrophenol, respectively. In control animals, SWR/J mice exhibited higher hepatic EROD activity (1.4-fold) when compared with AKR/J mice. In carcinogen-treated animals, EROD activity was decreased 20-30% in both mouse lines. Hepatic p-nitrophenol hydroxylase activity, similar in control animals of both strains, was reduced comparably (45-50% of control) after DMH administration. In liver, a decrease in immunoreactive Cyp2e1 protein paralleled the decline in enzyme activity, whereas in the colon, no significant treatment-related differences were detected in either strain. In liver and colon cytosols, alcohol dehydrogenase activity was not significantly different in either mouse line, both in control and DMH-treated animals. Glutathione levels were elevated (1.7-fold) in livers of AKR/J mice after DMH administration. Total glutathione-S-transferase (GST) activity was significantly increased (1.8-fold) in the colons of SWR/J mice and in the livers (1.4-fold) of AKR/J mice. Furthermore, the GST isoform, GST-Yp, was reduced 40% in the SWR/J colon. These data demonstrate the importance of metabolic capacity as a factor in conferring differential tumor susceptibility in a murine cancer model to the indirect-acting colon carcinogen, DMH.

1,2-Dimethylhydrazine↗

Management of colon ischemia following colon interposition for esophageal substitution.

During the past four years three patients have been seen with ischemia of the colon segment following colon interposition. Colon interposition was done for esophageal cancer in two patients and for esophageal stricture following ingestion of lye. Colon ischemia was manifested as early as two weeks in one patient and as late as eight weeks in the others. Colon ischemia presented a frank gangrene with cervical fistula or as dysphagia due to stricture formation. Dysphagia in two patients prompted mechanical dilatation of the colon segment which led to perforation in both cases. All three patients had empyemas. The management of these patients includes proper diagnosis, drainage of abscesses and antibiotic treatment, hyperalimentation and visceral arteriography to delineate the residual colon for reinterposition. Two of the three patients in the series are long-term survivors and are well.

Abscess↗

Expression of hormone receptors, cathepsin D, and HER-2/neu oncoprotein in normal colon and colonic disease.

BACKGROUND: Chronic ulcerative colitis and familial adenomatous polyposis are associated with an increased risk of colorectal carcinoma. Currently, there are no reliable methods to assess carcinoma risk. METHODS: Several prognostic factors known to be useful in breast carcinoma were determined in 102 specimens of colonic mucosa from 38 patients: 22 specimens from "normal," non-neoplastic colon, 49 from chronic ulcerative colitis, 10 from Crohn's colitis, 14 from familial adenomatous polyposis, four from mucosa adjacent to carcinoma, and three from colon carcinoma. Expression of estrogen receptor, progestin receptor, epidermal growth factor receptor, HER-2/neu (c-erb B-2) oncoprotein, and cathepsin D were determined. RESULTS: Epidermal growth factor receptor expression was higher in chronic ulcerative colitis, Crohn's colitis, familial adenomatous polyposis, and colon carcinoma and varied with location within the colon for chronic ulcerative colitis, Crohn's colitis, and familial adenomatous polyposis. Epidermal growth factor receptor expression in mucosa adjacent to carcinoma was similar to that in "normal" colon. CONCLUSION: Further analyses are needed to determine which parameters are related to and possibly predictive of increased carcinoma risk.

Adenomatous Polyposis Coli↗

Colonic lymphoid follicles associated with colonic neoplasms.

In 3,399 patients more than 40 years of age undergoing air-contrast enema examinations a prospective evaluation was done for the presence of colonic lymphoid follicles. In 3,315 patients there was no evidence of lymphoid follicles. Colonic neoplasms were diagnosed in 8.47% of these individuals. Eighty-four patients were found to have radiographically identifiable follicles. Fifty-eight of these 84 patients (69%) with lymphoid follicles had a synchronous (n = 19) or previous (n = 14) colonic neoplasm or a synchronous (n = 24) or previous (n = 1) colonic polyp. There were no consistent clinical or radiographic features that distinguished the patients with and without a neoplastic association. However, 90% of men with lymphoid follicles had associated neoplasms, whereas only 58% of women did. Because of the frequent association, detection of colonic lymphoid follicles in patients in this age group should lead to a vigorous search for subtle colonic neoplasms that may not be apparent because of technical limitations of the study.

Adult↗

Long-term-cultured colon epithelial cell lines from individuals with and without colon cancer genotypes.

In 1982 the characteristics of the first epithelial line established from normal human colon mucosa were reported. The purpose of this report is to describe 5 additional lines established from individuals with and without genotypes associated with genetic predisposition for colon cancer [1 familial polyposis coli (FPC) patient, 1 hereditary nonpolyposis colon cancer (HNPCC) patient, 2 clinically normal individuals (each at risk for one of these autosomal dominant syndromes), and 1 clinically normal individual without any family history of cancer]. The cultured cell lines had the morphologic features associated with epithelium as previously described in the 1982 report. The cell lines derived from genetically (FPC or HNPCC) predisposed individuals had three distinctive characteristics as compared to those derived from individuals without a family history of colon cancer: 1) a higher saturation density (P less than .01); 2) increased in vitro tetraploidy, an in vitro biomarker associated with genetic predisposition for colon cancer; and 3) a higher concentration of carcinoembryonic antigens (CEA) in their conditioned culture medium (P less than .01). Lines derived from normal individuals at risk for the same syndromes were found to have an increased risk status on the first two characteristics. However, the level of CEA did not increase in their culture media, which suggested that the increase in CEA was related to mucosal changes occurring in the preneoplastic sequence in colon cancer.

Adolescent↗

beta-Carotene supplementation results in an increased serum and colonic mucosal concentration of beta-carotene and a decrease in alpha-tocopherol concentration in patients with colonic neoplasia.

The aim of this study was to evaluate the colonic mucosal beta-carotene (BC) concentration following supplementation with BC and to determine if an increase in BC concentration influences vitamin E (alpha-tocopherol) status. The concentration of BC and alpha-tocopherol was assessed in serum and colonic tissue obtained from subjects with a history of colonic polyps or resected cancer (Dukes A, B1, or B2). Serum and mucosal biopsy samples were obtained prior to and following 3 months daily p.o. supplementation with 30 mg of BC or placebo. The concentration of BC was significantly increased in serum and colonic mucosa from both polyp and cancer subjects following supplementation as compared to presupplementation values and values from subjects receiving a placebo. The concentration of alpha-tocopherol in serum from cancer subjects was significantly decreased in samples obtained at the end of 3 months of BC supplementation as compared to placebo-matched controls. In BC-supplemented polyp subjects the tissue concentration of alpha-tocopherol was also significantly decreased relative to presupplementation values. The results indicate that BC supplementation does result in a significant accumulation of BC in the colonic mucosa but that the alpha-tocopherol concentration in both serum and colonic tissue may be compromised by an increased intake of BC. The mechanism for the decrease in alpha-tocopherol in conjunction with the increase in BC will require further study in order to develop strategies which will prevent vitamin E deficiency in BC-supplemented individuals.

Adult↗

Colonization pattern of the digestive tract by potentially pathogenic microorganisms: colonization-controlling mechanisms and consequences for antibiotic treatment.

An outline is given of the various host-related and flora-related parts of the colonization resistance of the digestive tract. The host-related part of the colonization resistance has been found to be somewhat decreased by sublethal irradiation and leukemia (or chemotherapy), while treatment with antibiotics active against gram-positive flora may severely decrease the colonization resistance (depending on the antibiotic concentration established within the digestive tract during antibiotic therapy). The flora-related part of the colonization resistance, which controls colonization by potentially pathogenic microorganisms, differs greatly from one individual to the next. This observation appears to be important for the host-related part of the colonization resistance. Finally, it is concluded that in the clinical situation preference should be given to antibiotics which do not affect the part of the flora constituting colonization resistance for two reasons: 1) to limit the spread of (multi-) resistant potentially pathogenic microorganisms and 2) for infection prophylaxis in immunocompromised patients. In the latter situation, the potentially pathogenic microorganisms in the flora are selectively eliminated from the digestive tract, provided the antimicrobial drugs used for selective decontamination are active against the endogenous potentially pathogenic microorganisms and given in sufficient (oral) doses.

Animals↗

Ectopic colonic mucosa in ulcerative colitis and in Crohn's disease of the colon.

Colectomy specimens from 62 patients (22 with ulcerative colitis, 20 with Crohn's disease of the colon, and 20 with invasive adenocarcinoma [without inflammatory bowel disease]) were reviewed for the presence of ectopic colonic mucosa. One or more foci of ectopic colonic mucosa were found in 16 of the 22 specimens (72 per cent) with ulcerative colitis and in 11 of the 20 specimens (55 per cent) with Crohn's disease of the colon. None of the 20 specimens having adenocarcinoma (without chronic inflammatory bowel disease) had ectopic colonic epithelium. The presence of ectopic colonic mucosa was found to be dependent on the age of the patients (more frequent among younger patients) and on the number of sections per specimen. One adenocarcinoma in a case of long-standing ulcerative colitis had apparently originated in ectopic colonic mucosa.

Adolescent↗

Prevalence of colonization with antibiotic resistant gram-negative bacilli in a nursing home care unit: the importance of cross-colonization as documented by plasmid analysis.

A prevalence study was carried out on a 100-bed Veterans Administration nursing home care unit to determine the extent of colonization with gentamicin-resistant gram-negative bacilli (GRGNB). Hand cultures of 12 employees and 17 environmental cultures were negative. Twenty-six of 86 (30%) patients were colonized with 49 GRGNB. Sixteen patients (19%) had urinary colonization. Multivariate analysis revealed significant associations between rectal or perineal colonization (P less than 0.01), and the presence of a urinary device (82% condom catheters) (P less than 0.05), with urinary colonization. The most common isolates were Providencia stuartii (20), Escherichia coli (nine) and Klebsiella pneumoniae (nine). Twenty-six of 49 isolates carried plasmids. Restriction endonuclease digestion of plasmid DNA was performed for 21. Cross-colonization, as defined by the presence of the identical species with the identical restriction endonuclease digestion profile of purified plasmid DNA found in different patients, was observed for eight of 21 (38%) strains. All were geographically clustered. No strains could transfer gentamicin-resistance by conjugation and only two plasmids could transform our E coli recipient to gentamicin resistance. One E coli plasmid was identical to two Citrobacter freundii plasmids and a P stuartii plasmid isolated from three different patients. This 105 kb plasmid is conjugative and encodes resistance to ampicillin, carbenicillin, tetracycline, and sulfonamides. Thus, 57% of strains were cross-colonizing or contained identical R-plasmids. Southern hybridization using a 1 kb TEM-1 gene probe demonstrated sequences homologous to this probe in five of five nursing home plasmids examined.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗

The colon cancer burden of genetically defined hereditary nonpolyposis colon cancer.

BACKGROUND & AIMS: Estimates of the frequency of hereditary nonpolyposis colon cancer (HNPCC) based on clinical criteria have varied widely. Recent studies of germline mismatch repair gene mutations have suggested that HNPCC accounts for close to 3% of all colon cancer, but this estimate may have been inflated by inclusion of founder effects peculiar to Finland. We therefore determined by genetic criteria the colon cancer burden associated with HNPCC in a population-based study of 1066 individuals from Utah and California. METHODS: The coding regions of mismatch repair genes hMSH2 and hMLH1 were sequenced from the germline of those individuals whose tumors exhibited microsatellite instability. RESULTS: Microsatellite instability was present in 16% (171/1066) of tumors. Pathogenic germline mismatch repair gene mutations were identified in 7 individuals, and missense amino acid changes of uncertain significance were identified in another 6 individuals. After adjusting for the availability of sufficient germline DNA for sequencing, the 7 clearly pathogenic mutations accounted for 0.86% of colon cancer at the population level. Individuals with these mutations were significantly younger, more likely to have a family history of colon and endometrial cancer, and more likely to have first-degree relatives with a young-age onset of colon cancer than individuals with unstable tumors but without germline mutations (P < 0.01). CONCLUSIONS: We conclude that genetically defined HNPCC accounts for a very small percentage of colon cancer at the population level, a percentage less than that estimated by most previous clinical studies.

Adaptor Proteins, Signal Transducing↗

Colonization and cross-colonization of nursing home patients with trimethoprim-resistant gram-negative bacilli.

A prospective study of 67 patients in a nursing home and a subpopulation of 31 patients who were stratified according to functional level--a general measure of the amount of nursing care required by the patients--was performed. The goals of this study were (1) to determine whether antibiotic selection of resistant variants from within endogenous flora of hosts or horizontal transmission is more important in the development of colonization with trimethoprim-resistant gram-negative bacilli (TRGNB) in a nursing home; (2) to identify the mode(s) of transmission if horizontal transmission is more important; and (3) to identify risk factors for colonization and cross-colonization with TRGNB. Although a number of variables were associated with colonization, only a decreased functional level appeared to be independently associated with colonization. Isolates from the subpopulation were subtyped by restriction endonuclease digestion of cellular DNA, as were isolates from personnel of the nursing home. Results revealed that 16 of 21 staff members had 48 positive cultures for TRGNB. Of 25 typeable isolates, 12 from seven of the 21 staff members were identical to patient strains. Analysis of acquisition of new strains of TRGNB by members of the subpopulation showed that 67.5% were the result of cross-colonization. Our data are consistent with, but do not prove, the hypothesis that nurses' hands are the primary mode of transmission of TRGNB in this nursing home and suggest that most colonization could be prevented by interdicting horizontal transmission.

DNA, Bacterial↗

Colonization of porcine small intestine by Escherichia coli: colonization and adhesion factors of pig enteropathogens that lack K88.

The colonizing and adhesive attributes of enterotoxigenic acapsular and/or nonpiliated mutants from K88-negative enteropathogenic Escherichia coli strains were compared with their capsulated and piliated parents (parents were piliated when grown in vitro and in vivo). Acapsular, nonpiliated mutants from three different colonizing strains of enteropathogenic E. coli lost their ability to colonize the ileum of newborn pigs. Acapsular, piliated and capsular, nonpiliated mutants were derived from one of the parental strains (987), and both mutants lacked the ability to colonize the ileum of pigs. The only mutants available from a fourth strain (431) were acapsular and piliated, and they colonized as well as their parents. These data indicate that both capsule and pili are involved in colonization by strain 987. In contrast, capsule is not required for colonization by strain 431, but pili may be.

Animals↗

Reduction of Campylobacter jejuni colonization of chicks by cecum-colonizing bacteria producing anti-C. jejuni metabolites.

Cecum-colonizing bacteria were isolated from Campylobacter jejuni-free White Leghorn (Gallus domesticus) laying hens and screened for the ability to produce anti-C. jejuni metabolites. Nine isolates were obtained that possessed this characteristic. The peroral administration of the nine isolates as a mixture (ca. 10(9) per chick) to 1-day-old chicks was followed 1 week later by peroral inoculation of Campylobacter jejuni (ca. 10(9) per chick) to determine if the cecal isolates could protect chicks from colonization by campylobacters. The nine-strain mixture of cecal bacteria provided from 41 to 85% protection from C. jejuni colonization. The protective bacteria were reduced to a mixture of three strains on the basis of their ability to utilize mucin as a sole substrate for growth. These strains included Klebsiella pneumoniae 23, Citrobacter diversus 22, and Escherichia coli (O13:H-) 25. Four feeding trials with this three-strain mixture provided from 43 to 100% (average, 78%) protection from C. jejuni colonization. The dominant cecal bacterium of chicks treated with the three-strain mixture was consistently E. coli O13:H-. Similarly, three trials with only E. coli 25 used as the protective bacterium resulted in 49 to 72% (average, 59%) protection from C. jejuni colonization, with E. coli O13:H- being the dominant cecal bacterium in all cases. Although not completely effective, E. coli 25 substantially reduced the incidence of C. jejuni colonization of chicks. For all trials, fewer C. jejuni were present in the ceca of colonized chicks receiving the protective bacteria before exposure to C. jejuni than in chicks receiving only C. jejuni.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

Net fluid secretion and impaired villous function induced by colonization of the small intestine by nontoxigenic colonizing Escherichia coli.

The role of colonizing bacteria in the small bowel in causing diarrhea remains unclear. We examined whether colonizing, nontoxigenic Escherichia coli could alter small bowel function by determining net water and electrolyte fluxes and sucrase activity in colonized and noncolonized ileal segments by using the reversible-ileal-tie adult rabbit model. Colonization of the ileum with nontoxigenic E. coli for greater than or equal to 72 h at greater than or equal to 10(4)/cm2 was associated with significant functional derangements, as follows: (i) overt liquid diarrhea in 50% of animals colonized at greater than 10(4)/cm2; (ii) reversal of normal net ileal absorption to net secretion of water, sodium, and chloride; and (iii) significant decrease in mucosal sucrase activity. We conclude that small bowel colonization by colonizing, nontoxigenic E. coli impairs water and electrolyte absorption and sucrase activity in the absence of recognized enterotoxin, cytotoxin, invasion, or effacement traits.

Animals↗

The major colonic cell mitogen extractable from colonic mucosa is an N terminally extended form of basic fibroblast growth factor.

Colonic growth factors (CGFs) were extracted from porcine intestinal epithelium and mucosa. Under acidic conditions, very little mitogenic activity (as assayed using murine 3T3 fibroblasts and a human colonic cell line) was extractable. However, by extracting at neutral or slightly alkaline pH, significant mitogenic activity for both the murine fibroblasts and human colonic carcinoma cell line could be detected. CGFs are present throughout the intestine and cecum. The epithelial mucosa of the distal colorectal region appeared to contain mitogens which were more potent for the colonic cells than the 3T3 fibroblasts. Purification of CGFs from the colonic mucosa required removal of associated mucin by pH precipitation prior to chromatographic fractionation. It was then possible to develop a complete purification (390,000-fold) scheme for the major CGF, an 18-kDa protein which bound to heparin-Sepharose. N-terminal sequence analysis yielded a single sequence (Q)SPGGAMAAGSITTLPALP, i.e. an N-terminally extended form of basic fibroblast growth factor. Apart from the substitution of Gly in bovine basic fibroblast growth factor by a Ser in porcine CGF, the proteins are identical. A similar extraction procedure using purified human colonic crypt epithelial cells yielded a mitogen for the human colonic cell line with similar chromatographic properties.

Amino Acid Sequence↗