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Studies of the enteric nervous system in Alzheimer disease and other dementias of the elderly: enteric neurons in Alzheimer disease.

Studies of the myenteric (Auerbach) plexus of esophagus, stomach, small intestine, colon, and rectum, by microdissection and pointcount morphometry, for 18 patients with Alzheimer disease (AD), eight with other types of dementia of the elderly, non-demented elderly patients, and younger control patients, show a normal loss of enteric neurons and plexus mass with age, comparable to that reported by others for rats and guinea pigs. Values for patients with AD or other non-AD dementias did not differ from those for elderly controls. Enteric neurons in AD or the other dementias studied showed no definite stain with ALZ-50, a monoclonal antibody to a derivative of the microtubule-associated protein tau, which stains degenerating cerebral neurons in AD. Although the processes in the central nervous system in AD affect some neurons derived from the neural plate, the results of this study suggest that the enteric neurons, which are of neural crest origin, are not affected in AD. Enteric neurons, at least by the methods of this study, do not provide a useful peripheral marker for AD.

Age Factors↗

Identification of a novel serine protease-like gene, the expression of which is down-regulated during breast cancer progression.

In an effort to isolate genes with down-regulated expression at the mRNA level during oncogenic transformation of human mammary epithelial cells (MECs), we performed subtractive hybridization between normal MEC strain 76N and its radiation-transformed tumorigenic derivative 76R-30. Here, we report the isolation of cDNA clones corresponding to a 1.4-kb mRNA species that is abundantly expressed in 76N cells but is drastically reduced in 76R-30 cells. Based on its selective expression in MECs compared with fibroblasts, the corresponding gene is designated NES1 (normal epithelial cell-specific 1). Sequence analysis of the full-length NES1 cDNA clones revealed it to be a novel gene with a predicted polypeptide of 30.14 kilodaltons; in vitro transcription and translation confirmed this prediction. Database searches revealed a 50-63% similarity and 34-42% identity with several families of serine proteases, in particular the trypsin-like proteases, members of the glandular kallikrein family (including prostate-specific antigen, nerve growth factor gamma, and epidermal growth factor-binding protein) and the activators for the kringle family proteins (including the human tissue plasminogen activator and human hepatocyte growth factor activator). Importantly, all of the residues known to be crucial for substrate binding, specificity, and catalysis by the serine proteases are conserved in the predicted NES1 protein, suggesting that it may be a protease. An antipeptide antibody directed against a unique region of the NES1 protein (amino acids 120-137) detected a specific 30-kilodalton polypeptide almost exclusively in the supernatant of the mRNA-positive MECs, suggesting that NES1 is a secreted protein. The 1.4-kb NES1 mRNA was expressed in several organs (thymus, prostate, testis, ovary, small intestine, colon, heart, lung, and pancreas) with highest levels in the ovary; a 1.1-kb transcript was found in the pancreas. Although expression of the NES1 mRNA was observed in all normal and immortalized nontumorigenic MECs, the majority of human breast cancer cell lines showed a drastic reduction or a complete lack of its expression. The structural similarity of NES1 to polypeptides known to regulate growth factor activity and a negative correlation of NES1 expression with breast oncogenesis suggest a direct or indirect role for this novel protease-like gene product in the suppression of tumorigenesis.

Amino Acid Sequence↗

The endothelin receptor is a major determinant for the nonlinear tissue distribution of the endothelin antagonist BQ-123.

The nonlinearity in the pharmacokinetics of the cyclopentapeptide endothelin antagonist BQ-123 was studied. Both the total body clearance and tissue-to-plasma concentration ratio (Kp) were investigated in rats under a wide range of steady-state plasma concentrations (Cpss) obtained by changing the intravenous infusion rate of BQ-123. The total body clearance was constant up to a Cpss level of 50 microM, although it was markedly decreased at higher Cpss values, which suggests the existence of a saturable elimination mechanism. A Cpss-dependent nonlinearity in the apparent Kp values (Kp,app) was clearly observed in many organs including lung, heart, spleen, pancreas, adrenal, stomach, intestine, colon, aorta, testis and muscle, where the endothelin ET(A) receptor is known to be localized. By fitting the saturation curves of the Kp,app values, a similar dissociation constant (Kd) was obtained for most organs at 5 to 10 nM, which is close to the reported Kd values of BQ-123 for the endothelin ET(A) receptor. The saturable portion of the Kp,app values observed in vivo showed a good correlation with reported values of the endothelin ET(A) receptor density. Binding of BQ-123 to isolated membrane fractions from several organs demonstrated clear saturability for the lung, heart, spleen and liver with Kd values of 1 to 3 nM. Such specific binding also showed a good correlation with the saturable portion of the Kp,app values. From these results, we concluded that the endothelin receptor(s) is responsible for the nonlinear tissue distribution of BQ-123 in rats.

Animals↗

Whipple's disease: a non-invasive approach for suspected diagnosis. Case report.

A case is presented of Whipple's disease with mild gastrointestinal symptoms. Abdominal ultrasonography and breath test after lactose load were of great help in the diagnostic phase and follow-up. Ultrasonography showed dilated and thickened ansae and abdominal lymph nodes which were considerably increased in volume and markedly hyperechoic; this latter aspect would seem to be typical of lymph adenomegalia secondary to Whipple's disease and is linked to the accumulation of fats. The breath test showed two H2 peaks, the first being early (30 min after lactose intake) suggesting high seated bacterial colonization. Intestinal biopsy confirmed the diagnosis of Whipple's disease. After 40 days of antibiotic treatment the clinical and laboratory pictures were almost normal and the breath test showed complete disappearance of H2 production, thus confirming the effectiveness of the treatment in eradicating the intestinal bacteria.

Adult↗

[Fungal infections in primary care].

Fungal infections are of minor importance in general practice. With the possible exception of cryptococcosis in HIV-infected patients deep fungal infections are rarely seen in ambulatory medicine. Some exceptions are discussed. Candida spp. are normally found on the surfaces of the gastrointestinal and genital tract. The documentation of yeast from these sites is therefore not an indication for antifungal therapy. Esophagitis oral or vaginal thrush should however be treated promptly with oral fluconazole. Cutaneous mycoses are best treated topically or if too extensive with itraconazole or terbinafine. Treatment of nail infection, if treatment is warranted at all is best treated with terbinafine. Any attempts to attribute uncharacteristic complaints to an intestinal colonization with yeasts or nutritional fungal toxins lacks a scientific background. The practice to diagnose from blood films obscure fungal infections is quackery at best.

Antifungal Agents↗

[Possibility of alpha-tricalcium phosphate (alpha-TCP) particles as a drug carrier for treatment of abdominal carcinomatosis].

It is reported that cancer foci are unevenly distributed in abdominal carcinomatosis after intraperitoneal inoculation of cancer cells in rats. The organs may be briefly classified into two groups in terms of the deposit of cancer cells: one that shows an affinity to the cells includes the greater omentum, mesenterium, and gonadal fat and etc., and the other having lesser affinity the stomach, intestine, and spleen and etc. Such uneven distributions are likely to occur in clinical cases of abdominal carcinomatosis resulting from progressive digestive cancers. We have explored the possibility of alpha-Tricalcium Phosphate (alpha-TCP) particles as a drug carrier in which carboplatin (CBDCA) was incorporated. alpha-TCP, which has chemically similar properties to hydroxyapatite, is known to have an excellent biocompatibility with human tissues and is biodegradable. The present study focused on the localization and the forms of alpha-TCP particles, and the morphological changes of the surrounding tissues after intraperitoneal administration using normal and cancer-bearing rats. The following results were obtained: (1) alpha-TCP particles were taken up to a large extent in the "milky spot" of the greater omentum, followed by the "stomata" of the mesenterium, gonadal fat, diaphragm, peritoneum, and liver in normal rats. No alpha-TCP particles were caught up in the tissues of the stomach, small intestine, colon, and spleen. The margination and emigration of lymphocytes were slightly observed around those organs. (2) alpha-TCP particles were predominantly detected on the cancer mass of the greater omentum in abdominal carcinomatosis-bearing rats. It should be noted that the particles collected in the same place where cancer cells were caught, suggesting that the localization of the drug-containing particles result in higher drug concentrations in the cells possibly for extended times. The alpha-TCP particles system is expected to be a good candidate for targeting chemotherapy and specially for abdominal carcinomatosis.

Abdominal Neoplasms↗

[Prophylaxis of intestinal paresis after colon surgery].

In the clinic, a method for prophylaxis of postoperative intestinal paresis with the use of local consecutive electroimpulse influencing upon the zones--pacemakers of the small and large intestine by a current with a frequency corresponding to the physiologic frequency of contractions of a given intestinal segment at the time corresponding to the physiologic one in restoration of motor activity of the intestine have been developed. Electric stimulation of a pacemaker contributes to organization and synchronization of activity of the neural ganglia and amplification of their myoelectrical signal. As a result, the activity of proximal pacemakers predominates over that of the distal ones and contributes to restoration of a gradient of propulsive activity. The method was employed in 53 patients. The time of restoration of peristaltic and propulsive functions of the intestine corresponded to the physiologically substantiated time.

Colon↗

Intestinal lymphangiectasia and colonic polyps: surgical intervention.

A 36-mo-old boy with Milroy's Disease, intestinal lymphangiectasia, and an exudative enteropathy (EE), was shown to have four colonic polyps. A large adenomatous polyp was excised from the transverse colon in an effort to control his EE and hypoalbuminemia (1.95 g/dl). His clinical status then stabilized until age 50 mo when there was a marked exacerbation of his EE. Medical management resulted in a temporary stabilization of his condition. A partial resection (40 cm) of the visually worse affected jejunum was performed. There was no improvement in the EE as measured by 51Cr-tagged albumin study; however, his clinical response was dramatic. In the 10 mo since surgery, he has been well and has shown catchup in linear growth.

Child, Preschool↗

Alteration of sulfate and hydrogen metabolism in the human colon by changing intestinal transit rate.

OBJECTIVES: Changes in intestinal transit rate are also implicated in the etiology of many colonic diseases and strongly influence many metabolic processes in the colon. We set out to investigate whether intestinal transit time could influence the activity of the hydrogen-consuming bacterial flora and sulfate metabolism. METHODS: Normal volunteers underwent four interventions while taking a low-sulfate diet: placebo, sulfate supplements, or sulfate supplements with either senna or loperamide. Stools were cultured and analyzed for sulfate, sulfide, methionine, sulfate reduction rates, methionine reduction rates, acetic acid production rates, methane production rates, short-chain fatty acids, and bile acids. Urine was analyzed for sulfate. RESULTS: The addition of sulfate alone increased fecal and urinary excretion of sulfate, fecal sulfide, sulfate reduction rates, and acetic acid production rates; it reduced fecal methanogenic bacterial concentrations. Faster intestinal transit increased fecal sulfate, sulfide, bile acids, the reduction rates of sulfate, and methionine and the production rates of acetic acid. Reduction in fecal methanogens and methane production was seen. The reverse effects were seen with loperamide. CONCLUSIONS: Both sulfate supplements and changes in intestinal transit rate markedly alter the activity of the colonic bacterial flora with respect to sulfate metabolism and hydrogen disposal. Dietary influences on intestinal transit and sulfate consumption may influence disease processes. While a variety of processes govern sulfate metabolism and hydrogen disposal, our knowledge is far from complete. How far the observed changes in sulfate metabolism seen in certain diseases are relevant to the pathogenesis of the disease or secondary to the disease itself is unclear.

Acetic Acid↗

[The role of flagella of Campylobacter jejuni in colonization in the intestinal tract in mice and the cultured-cell infectivity].

For analyzing the role of the bacterial flagella in colonization in the intestinal tract of mice and adhering to or invading the Intestine 407 cell, a nonflagellated, nonmotile mutant was induced by ultraviolet irradiation of a flagellated, motile wild-type strain of Campylobacter jejuni CF84-340. There was no great difference in the cellular infectivity to the Intestine 407 cells between the wild-type and the mutant strains. Cellular adherence and invasiveness were then compared by fluorescent antibody staining, and an obvious difference was found in the latter. While 21.4% of the organisms of the wied-type strain invaded the cells, only 6.1% of those of the flagella-defective mutant did so. In the experiments in mice involving oral administration, cellular invasiveness was not found with the flagella-defective mutant and no organisms were detected from the blood, although bacteremia is one of the characteristics of infection with C. jejuni. Moreover, no intestinal adherence of the mutant was detected, suggesting early elimination of the organism administered. These results indicate that the bacterial flagella are concerned in not only the cellular adherence and intestinal deposit, but also the intracellular invasiveness and invasion into the blood stream from the intestinal wall in the infected mice.

Animals↗

Eosinophilic gastroenteritis involving the distal small intestine and proximal colon.

Eosinophilic gastroenteritis (EG) is an unusual disorder. It is characterized by eosinophil infiltration of the gut wall histologically and is manifested by gastrointestinal (GI) symptoms clinically. This disease entity preferentially affects the stomach and proximal small intestine. Mucosal layer disease is the most common form of this uncommon disease. We present a case of EG with transmural distal small intestinal and proximal colonic involvement whose clinical symptoms included watery diarrhea, abdominal pain, and body weight loss. Colonoscopy showed non-specific colitis in the proximal colon. Small bowel series showed diffuse jejunal dilatation with wall thickening and rigidity. Abdominal computed tomography also showed a thickened bowel wall with partial ileus and ascites. Diagnosis was established through endoscopic biopsy and ascites paracentesis, while at the same time excluding the possibility of parasite infection. Treatment with prednisolone produced a dramatic response. A high index of suspicion in cases of peripheral eosinophilia with concomitant GI symptoms is needed for the early diagnosis of this uncommon disease.

Adult↗

Endoscopic appearance of the colon and small intestine of a patient with hemorrhagic enteric graft-vs.-host disease.

Endoscopic appearance of the gastrointestinal tract of a patient with severe hemorrhagic enteric graft-vs.-host disease (GVHD) is presented. A 29-year-old man with chronic myelogenous leukemia suffered from severe enteric GVHD after allogeneic bone marrow transplantation. Endoscopy showed hemorrhagic ulceration of the upper jejunum, terminal ileum, and colon at the onset of melena. Sections of biopsies were compatible with acute GVHD. Repeat endoscopy showed gradual healing of the lesions after steroid pulse and antilymphocyte globulin therapy, but the patient died of cytomegalovirus pneumonitis 14 months later. Autopsy revealed submucosal fibrosis of the small intestine and colon.

Adult↗

Atrial natriuretic peptide modulates cystic fibrosis transmembrane conductance regulator chloride channel expression in rat proximal colon and human intestinal epithelial cells.

The cystic fibrosis transmembrane conductance regulator (CFTR) is one of the most intensively investigated Cl- channels. Different mutations in the CFTR gene cause the disease cystic fibrosis (CF). CFTR is expressed in the apical membrane of various epithelial cells including the intestine. The major organ affected in CF patients is the lung, but it also causes an important dysfunction of intestinal ion transport. The modulation of CFTR mRNA expression by atrial natriuretic peptide (ANP) was investigated in rat proximal colon and in human intestinal CaCo-2 cells by RNase protection assay and semi-quantitative reverse transcriptase PCR techniques. Groups of rats subjected to volume expansion or intravenous infusion of synthetic ANP showed respective increases of 60 and 50% of CFTR mRNA expression in proximal colon. CFTR mRNA was also increased in cells treated with ANP, reaching a maximum effect at 10(-9) M ANP, probably via cGMP. ANP at 10(-9) M was also able to stimulate both the CFTR promoter region (by luciferase assay) and protein expression in CaCo-2 cells (by Western blot and immunoprecipitation/phosphorylation). These results suggested the involvement of ANP, a hormone involved with extracellular volume, in the expression of CFTR in rat proximal colon and CaCo-2 intestinal cells.

Animals↗

Klebsiella pneumoniae capsule expression is necessary for colonization of large intestines of streptomycin-treated mice.

The role of the Klebsiella pneumoniae capsular polysaccharide (K antigen) during colonization of the mouse large intestine was assessed with wild-type K. pneumoniae LM21 and its isogenic capsule-defective mutant. When bacterial strains were fed alone to mice, the capsulated bacteria persisted in the intestinal tract at levels of 10(8) CFU/g of feces while the capsule-defective strain colonized at low levels, 10(4) CFU/g of feces. In mixed-infection experiments, the mutant was rapidly outcompeted by the wild type. In situ hybridization on colonic sections revealed that bacterial cells of both strains were evenly distributed in the mucus layer at day 1 after infection, while at day 20 the wild type remained dispersed and the capsule-defective strain was seen in clusters in the mucus layer. These results suggest that capsular polysaccharide plays an important role in the gut colonization ability of K. pneumoniae.

Animals↗

The antibody response in breast-fed and non-breast-fed infants after artificial colonization of the intestine with Escherichia coli O83.

The local and systemic antibody response after oral administration of a nonenteropathogenic type 1 fimbriated Escherichia coli O83 strain was followed in nine breast-fed and eight formula-fed infants during their first 15 wk of life. Five breast-fed and six formula-fed infants were followed as controls. E. coli O83 was detected in the stools of colonized infants from d 2 after colonization and persisted in the intestine for up to 26 wk. The percentage of children successfully colonized with E. coli O83 was higher among breast-fed than among formula-fed colonized infants. Also, the O83 bacteria isolated from the breast-fed children had a higher capacity to attach to colonic epithelial cells of the HT-29 cell line than those isolated from bottle-fed infants. E. coli O83 IgA and IgM antibodies estimated by ELISA were significantly elevated in the saliva of colonized as compared with control infants 2-7 wk after colonization. IgA antibodies against O83 were also higher in the stool of colonized formula-fed infants than in formula-fed controls. The results suggest that the mucosal immune system of the newborn infant can be triggered early to produce specific antibodies against bacteria colonizing the intestine.

Antibodies, Bacterial↗