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Mucositis is a common toxicity of cancer chemotherapy. Glutamine appears to be the major energy source for intestinal epithelium, and animal studies have suggested that dietary supplementation with glutamine may protect the gut from both radiation and chemotherapy. Patients experiencing stomatitis after a course of chemotherapy were offered the opportunity to enter the current study if no clinical parameters precluded receiving the same chemotherapy doses during the next course of treatment. Patients received the same chemotherapy regimen as during the previous treatment but in addition received a suspension of L-glutamine, 4 gm swish and swallow twice a day, from day 1 of chemotherapy for 28 days or for 4 days past the resolution of any post-chemotherapy mucositis. Twelve patients receiving doxorubicin, 1 receiving etoposide, and 1 receiving ifosfamide, etoposide, and carboplatinum were entered into the study. The maximum grade (CALGB criteria) of mucositis decreased in 12 of 14 patients with glutamine supplementation (median score 2A vs 0.5, p < 0.001). Similarly, after glutamine supplementation, the total number of days of mucositis was decreased in 13 of 14 patients (2.7 +/- 0.8 (mean +/- SEM) vs 9.9 +/- 1.1, p > or = 0.001). Thirteen of the 14 patients felt that the mucositis was less severe with the addition of glutamine. No change in the nadir neutrophil count was noted with glutamine, and no toxicity of glutamine was observed. We conclude that oral supplementation with glutamine can significantly decrease the severity of chemotherapy-induced stomatitis, an important cause of morbidity in the treatment of patients with cancer. Glutamine supplementation in patients receiving therapy for cancer warrants further study.
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PMID:Oral glutamine to prevent chemotherapy induced stomatitis: a pilot study. 863 52

Enteric bacteria have been postulated to have a role in thyroid economy by promoting the hydrolysis of thyroid hormone conjugates of biliary origin, thus permitting the absorption and recycling of thyroxine (T4) and triiodothyronine (T3). An enterohepatic circulation of T3 might be more pronounced under conditions in which type I iodothyronine deiodinase activity (5'D-I) is inhibited, because this augments the accumulation of T3 sulfate conjugates in bile. This potential of increased gut reabsorption of T3 might explain, at least in part, the failure of serum T3 values to decrease appreciably when marked reductions in peripheral 5'D-I activity are induced by selenium deficiency or 6-anilino-2-thiouracil (ATU) administration. Thus, studies were performed to determine the effect of intestinal decontamination, in the absence and in the presence of 5'D-I inhibition, on plasma T4 and T3 concentrations. Groups of adult male rats received either enteric antibiotics or no antibiotics for 12 days and then, in half of the rats in each group, treatment for 10 days with ATU, a 5'D-I inhibitor that does not affect thyroid hormone synthesis. The activity of intestinal arylsulfatase and arylsulfotransferase, enzymes that catalyze hydrolysis of thyroid hormone conjugates, was reduced markedly by approximately 87% in rats that received antibiotics, regardless of whether or not they also received ATU. The ATU treatment markedly inhibited liver 5'D-I activity in antibiotic-treated as well as in non-antibiotic-treated rats (control = 399 +/- 32 U/mg protein (mean +/- SEM); ATU = 152 +/- 17: antibiotics = 351 +/- 29; antibiotics + ATU = 130 +/- 10; p < 0.01) and significantly increased plasma T4 and T3 sulfate (T4S, T3S) concentrations (control: T4S = 2.8 +/- 0.4 and T3S = 6.7 +/- 1.3 ng/dl; ATU: T4S = 6.2 +/- 1.4 and T3S = 10.6 +/- 2.1 ng/dl; antibiotics: T4S = 1.8 +/- 0.2 and T3S = 3.6 +/- 1.0 ng/dl; antibiotics + ATU: T4S = 6.8 +/- 0.7 and T3S = 9.7 +/- 1.8 ng/dl; p < 0.05). The ATU treatment was associated with a significant increase in plasma T4 and rT3 concentrations but did not affect plasma T3 concentrations, and intestinal decontamination did not alter these ATU-associated effects on circulating thyroid hormones. These results suggest that anaerobic enteric bacteria in the rat do not have an important role in recycling of thyroid hormones, either under normal conditions or in circumstances where 5'D-I activity is markedly reduced, and that increased gut absorption of T3 from T3S cannot explain the near-normal serum T3 values found when peripheral 5'D-I activity is markedly decreased.
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PMID:Serum iodothyronine concentrations in intestinally decontaminated rats treated with a 5'-deiodinase type I inhibitor 6-anilino-2-thiouracil. 864 Mar 7

Localised folate deficiency has been implicated in colonic carcinogenesis and supplementation has been proposed for certain populations at risk. However, identifying those groups that may benefit is difficult as the relation between blood folate and gut epithelial cell values is unknown. The aim of this study was to define this relation. Epithelial cells mean (SEM) (sigmoid: 5.35 (0.56) x 10(6) cells, caecum: 6.6 (0.71) x 10(6) cells, duodenum: 4.0 (0.62) x 10(6) cells) were isolated from four endoscopic mucosal biopsy specimens (n = 25) by incubation with dithiothreitol (three hours) and EDTA (one hour). Lamina propria contamination was < 1%, with < 6% intraepithelial lymphocytes. Folate assay of isolates showed sigmoid colon folate content to be 20.1 (1.8) pg/micrograms DNA (10.2-46.6). In the same subject, caecal folate concentrations were lower (p < 0.01, n = 11) than sigmoid values, whereas duodenal isolates mirrored those of the sigmoid (19.4 (2.9) v 20.5 (3.2), n = 5). Sigmoid folate values were consistent over one to three weeks (n = 3). In a single case with blood folate deficiency, colonic values were normal. Serum folate and red cell folate correlated poorly with sigmoid epithelial cell folate content (r = 0.41, p = 0.063 and r = 0.17, p > 0.05 respectively). This study reports a modified ion-chelation isolation method for colonic biopsy specimens that yields large numbers of viable epithelial cells. Cell folate values remain constant with time though vary with intestinal region. The inability of serum or red cell folate values to predict those of the sigmoid epithelium suggests that they cannot identify those patients that might benefit from folate supplements.
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PMID:Folate status of gastrointestinal epithelial cells is not predicted by serum and red cell folate values in replete subjects. 867 95

Hypoperfusion of the gut mucosa is thought to be a factor in the development of gut barrier failure during sepsis and septic shock. Dopamine stimulates DA-1 receptors which mediate regional vasodilatation in the gut. Therefore, we have investigated the effect of low-dose dopamine (3 micrograms kg-1 min-1) on the intestinal villus microcirculation during endotoxaemia in a rat model of normotensive endotoxaemia, using in vivo videomicroscopy. Blood flow in and the diameters of central villus arterioles were measured before, immediately after and 60 min after a 1-h continuous infusion of endotoxin 1.5 mg/kg body weight. After baseline measurements were obtained, rats received either an infusion of 0.9% saline (group A; n = 7) or a volume-equivalent infusion of dopamine 3 micrograms kg-1 min-1 (group B; n = 7) throughout the study. Control animals (group C; n = 7) received no endotoxin or dopamine. In group A, villus blood flow (mean baseline 8.4 (SEM 0.9) nl min-1) decreased by 29.7 (8.9)% to 5.9 (0.9) nl min-1 immediately after endotoxin challenge and by a total of 43.1 (7.3)% to 4.7 (0.7) nl min-1 after another 60 min. Simultaneously, villus arteriolar diameters decreased from 7.8 (0.2) to 6.9 (0.3) microns and to 6.5 (0.3) microns, respectively. In group B, villus blood flow (baseline 8.7 (0.4) nl min-1) was unchanged immediately after the 1-h infusion of endotoxin (8.3 (0.4) nl min-1). However, another 60 min later blood flow decreased by 28.8 (8.0)% to 6.1 (0.7) nl min-1. In contrast with group A, the diameters of the central villus arterioles were unchanged despite administration of endotoxin (7.9 (0.2) microns; 8.1 (0.4) microns; 8.2 (0.5) microns). In group C, there were no changes in villus blood flow or arteriolar diameters throughout the study. Our results indicated that low-dose dopamine did not prevent, but delayed and attenuated, the decrease in intestinal villus blood during normotensive endotoxaemia.
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PMID:Effect of low-dose dopamine on intestinal villus microcirculation during normotensive endotoxaemia in rats. 868 74

A chronic pig model was developed which permits the simultaneous measurement of integrated biliary motility as resistance to flow (CBD inflow), gallbladder, duodenal and gastric motility in addition to collection of venous blood samples for gut hormones estimations. Animals displayed a duodenal interdigestive cycle of 55.4 +/- 3.4 min (mean +/- SEM, n = 6), consisting of phase I, II and III (21.2 +/- 2.1, 70.5 +/- 2.0, 8.7 +/- 0.5% of the cycle, respectively). A gastric interdigestive cycle of 60.2 +/- 6.5 min (n = 4) was similarly demonstrated consisting of three phases which corresponded to the three duodenal phases. The gastric phases I, II and III comprised 26.3 +/- 3.0, 71.2 +/- 2.7 and 2.5 +/- 0.8% of the cycle, respectively. The gastric phase III immediately preceded the onset of the duodenal phase III. The gallbladder likewise displayed an interdigestive cycle of 54.5 +/- 7.2 min (n = 6) consisting of a quiescent period (37.2 +/- 3.7% of the cycle) corresponding temporally to duodenal phase III and phase I. This quiescent phase was followed by a period of rhythmic contractions (64.5 +/- 4.1% of the cycle) which corresponded temporally to duodenal phase II. The onset of the gallbladder quiescent period coincided with the onset of duodenal phase III. The CBD inflow similarly demonstrated an interdigestive cycle of 53.4 +/- 9.6 min (n = 4) duration, consisting of three phases. The initial phase was evident as a period of rapid inflow, the onset of which coincided with the onset of duodenal phase III and the gallbladder quiescent period, and occupied 12.0 +/- 0.8% of the cycle. The second phase which occupied 18.0 +/- 7.4% of the cycle, was typified as a period of declining inflow which reached a relatively stable level at a time corresponding to the end of duodenal phase I. The third phase consisted of the maintenance of the inflow rate achieved at the end of the previous phase (60% of maximum inflow), corresponding in onset and duration with duodenal phase II and occupied 70.0 +/- 8.6% of the cycle. Plasma motilin levels fluctuated in relation to the duodenal interdigestive cycle, peaking during phase III relative to phase I (36.9 +/- 8.5 vs 25.4 +/- 7.7 pg mL-1, respectively, n = 5, P < 0.05). Cholecystokinin levels did not fluctuate, remaining low (2.3 +/- 2.1 pM cholecystokinin octapeptide equivalents, n = 5) throughout the duodenal interdigestive cycle, but increased about two fold after ingestion of solid food. Feeding disrupted the gastric, duodenal, gallbladder and CBD inflow cycles.
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PMID:Coordination of biliary and upper gastrointestinal motility in the fasted conscious pig. 869 85

Absorption from the intestine of cyclosporin A (CsA), dissolved in either a medium-chain (MCT) or a long-chain triglyceride (LCT) solution, was investigated in a chronic dog model. Following intrajejunal administration of 20 mg of CsA/kg of body weight, absorption, judged by the portalvenous appearance of CsA, was determined by measuring whole blood CsA concentrations in the portalvenous and arterial blood and the portalvenous flow. Appearance of CsA from LCT commenced earlier and attained significantly higher mean peak values (+/- SEM) in the portalvenous blood (2557 +/- 436 ng/mL) than from MCT (274 +/- 80 ng/mL). Portalvenous concentrations of CsA were always higher than arterial concentrations for both LCT and MCT, suggesting that CsA is transported by portalvenous blood following uptake from the gut. Absorption of CsA, measured over 300 min, was 10 times higher with LCT (9.96 +/- 2.00%) than with MCT (0.95 +/- 0.21%). This significant difference is believed to result from the formation of mixed micelles which occurs during digestion of LCT but not MCT.
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PMID:Comparison of cyclosporin A absorption from LCT and MCT solutions following intrajejunal administration in conscious dogs. 877 66

Gut ischemia has been implicated in the pathogenesis of necrotizing enterocolitis. Cyclosporine A and rapamycin, both potent novel immunosuppressants which act on signal transduction pathways in CD4+ T-cells, could potentially modulate immune/inflammatory cellular reactions involved in tissue ischemia/reperfusion injury. We hypothesized that cyclosporine A and rapamycin would preserve mucosal cell function and attenuate inflammatory T-cell-mediated cellular changes associated with small bowel ischemic injury. Forty Sprague-Dawley rats underwent 60 min of gut ischemia by vascular occlusion of the superior mesenteric vessels. Animals were randomized to four groups (n = 10): cyclosporine A (CSA, 5 mg/kg/day SQ), rapamycin (RAP, 2 mg/kg/day SQ), cyclosporine A and rapamycin (C&R), and vehicle given to controls (CON). Following 1 hr of reperfusion, small bowel was harvested for xanthine oxidase (XO, units/mg protein) and maltase (MALT, mM substrate degraded/min/g protein) assays. Blood was obtained from the portal vein for tumor necrosis factor-alpha (TNF-alpha, pg/ml) assay. The results of the study are presented below (mean +/- SEM, *, P < 0.05 versus controls). (Table in text) The results indicate that cyclosporine and rapamycin each play a significant role in attenuating ischemia/reperfusion injury in the gut. These data suggest that there are cytoprotective and anti-inflammatory mechanisms of these drugs independent of T-cell signal transduction that provide some protective effect in small bowel ischemia. Furthermore, T-cell-mediated immune mechanisms may not be associated with the adverse effects of small bowel ischemia/reperfusion injury. Additional investigation will be necessary in order to define the role of T-cell-mediated immune injury in the gut and how this relates to the beneficial effect of immunosuppression in small bowel mucosal ischemic injury.
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PMID:Beneficial effects of cyclosporine and rapamycin in small bowel ischemic injury. 890 56

The incremental glucagon-like peptide 1 (GLP-1) and gastric inhibitory polypeptide (GIP) responses (areas under curves; AUCs) were determined during a standard 180-min 75-g oral glucose tolerance test in a group of 12 identical twin pairs discordant for non-insulin-dependent diabetes mellitus (NIDDM) and 13 matched controls without family history of diabetes using highly sensitive and specific radioimmunoassay hormone assays. Data were analysed using multifactor analysis of variance (ANOVA) to identify and correct for possible covariates and to correct for multiple comparisons. Fasting plasma GLP-1 and GIP concentrations were similar in all groups. The twins with frank NIDDM had a decreased incremental GLP-1 response during oral glucose ingestion compared with controls without family history of diabetes (AUC +/- SEM: 0.55 +/- 0.14 vs 1.17 +/- 0.25 (mmol/l) x min, p < 0.05). The incremental GLP-1 secretion in the non-diabetic twins was not significantly different from neither their NIDDM co-twins nor the controls without family history of diabetes. The incremental GIP responses were similar in all study groups. Gender was identified as the major independent covariate for incremental glucose, insulin, GIP and GLP-1 responses, with higher values of all parameters in females. Waist-to-hip ratio and body mass index (BMI) were identified as independent but oppositely directed covariates for the incremental GLP-1 responses (waist-to-hip ratio: r = 0.43, p < 0.02; BMI: r = -0.34, p = 0.06). Incremental GLP-1 responses correlated with incremental insulin responses in the combined study population (N = 37; R = 0.42, p = 0.01). In conclusion, a decreased intestinal GLP-1 secretion may contribute to the abnormal insulin secretion during oral glucose ingestion in NIDDM twins. However, decreased secretion of gut incretin hormones (GLP-1 or GIP) does not explain all of the defects of pancreatic insulin secretion in NIDDM patients/twins or in non-diabetic individuals (identical twins) with a genetic predisposition to NIDDM.
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PMID:Gut incretin hormones in identical twins discordant for non-insulin-dependent diabetes mellitus (NIDDM)--evidence for decreased glucagon-like peptide 1 secretion during oral glucose ingestion in NIDDM twins. 892 24

To our knowledge postoperative hepatic hemodynamics and hepatic metabolism have not been fully studied on a long-term basis. Our goal was to develop a large animal model that would permit the measurement of hepatic blood flow (BF), perihepatic pressures (P), and hepatic metabolism in a long-term setting. Catheters were inserted into the jugular vein, carotid artery, pulmonary artery, hepatic vein, and portal vein (PV) of 27 commercially bred pigs; ultrasonic transit time flowmeter probes were placed around the hepatic artery and PV. Daily postoperative measurements of jugular vein P, carotid artery P, pulmonary artery P, hepatic vein P, and PVP, as well as hepatic artery BF and PVBF, were recorded for 20 days. Hepatic carbohydrate metabolism was assessed by arteriovenous difference techniques. Jugular vein P, pulmonary artery P, hepatic vein P, PVP, and heart rate reached steady-state values during the first week, with a mean +/- SEM of 1.0 +/- 0.3 mm Hg for jugular vein P, 21.4 +/- 2.1 mm Hg for pulmonary artery P, 4.3 +/- 0.4 mm Hg for HVP, 7.8 +/- 0.5 mm Hg for PVP, and 116 +/- 4 beats per minute for heart rate. Mean carotid artery P increased from 65 +/- 3 mm Hg during surgery to 94 +/- 2 mm Hg on postoperative day 1 (P < 0.001) and to a mean 101 +/- 2 mm Hg thereafter. Total hepatic BF reached a steady-state value of 1,132 +/- 187 ml/min by postoperative day 7 (P = 0.19). Over week 1 hepatic artery BF measured as a percentage of total hepatic BF decreased from 35.0 +/- 3.0% to 15.5 +/- 2.7%, and PVBF increased from 65.0 +/- 3.0% to 84.5 +/- 2.7% (P < 0.005); both variables were steady thereafter. In the hemodynamic steady state the net hepatic balances of glucose, lactate, glycerol, and alanine in 5 pigs were 9.9 +/- 4.0, -4.2 +/- 0.4, -2.3 +/- 1.1, and -0.68 +/- 0.22 micromol/kg per min respectively. The net gut (portal-drained viscera) balances of glucose, lactate, alanine, and glycerol were -2.0 +/- 2.5, 1.1 +/- 0.5, 0.73 +/- 0.18, and -0.69 +/- 0.19 micromol/kg per min respectively. Thus, a reliable large animal model was developed to study acute and chronic hepatic hemodynamics and metabolism.
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PMID:A model for the extended studies of hepatic hemodynamics and metabolism in swine. 900 Nov 78

Whole-body and splanchnic protein metabolism were determined in six young (mean age: 22.7 y) and six old (68.2 y) men before and during a standardized meal (41.8 kJ/kg) containing 15.6% protein, by using a combination of intravenous ([13C]leucine) and oral ([2H3]leucine) tracers. In the postabsorptive state, leucine flux and oxidation were similar in both groups when corrected for lean body mass (mean +/- SEM: 1.80 +/- 0.09 compared with 1.79 +/- 0.07 mumol.kg-1.min-1 and 0.55 +/- 0.02 compared with 0.49 +/- 0.04 mumol.kg-1.min-1 for young and old men, respectively, NS). The pattern of response to the meal was also similar in young and old men: increased flux and oxidation, decreased protein breakdown, and unchanged protein synthesis. Splanchnic extraction of dietary leucine was twice as high in elderly men (50 +/- 11% compared with 23 +/- 2%, P < 0.05), was inversely related to plasma leucine concentration (r = -0.771, P < 0.01), and was positively related to body mass index (r = 0.861, P < 0.001). In conclusion, in elderly men there is higher leucine extraction by the gut, liver, or both during feeding, which could lead to a lower peripheral availability of dietary leucine.
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PMID:Splanchnic and whole-body leucine kinetics in young and elderly men. 902 34


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