The intestinal phase of gastric secretion. Response to liver extract infusion into the proximal jejunum of healthy human subjects

A Levine tube was placed under radiological control in the stomach, and a thin polyethylene tube in the proximal jejunum of 6 healthy volunteers. The stomach and proximal part of jejunum were perfused for 2 hours with 1% acetylcholine, 20% meat extract (Bovril), and 15% liver extract (LE) alone and in combination with simultaneous infusion of different doses of exogenous pentagastrin intravenously. A significant increase in serum gastrin concentration was found with antral perfusion of LE only, whereas perfusion of the proximal jejunum did not change the basal level of the serum gastrin concentration. No change from control values was observed in gastric acid, and pepsin output on perfusing proximal jejunum with LE alone, or in combination with pentagastrin. Reflux to the stomach varied between 0-1.4%, as determined by addition of radioactive B12 to the perfusates. The experiments showed that gastrin was released from the antrum of the stomach by perfusion with 15 per cent LE, but not from the jejunum under the present experimental conditions. In the present experiments Bovril and acetylcholine perfusions did not cause significant responses from the antrum or from the proximal jejunum.     

Effect of caffeine on the human small intestine

Methylxanthines produce intracellular accumulation of cyclic 3'5'-AMP (cAMP) by inhibition of phosphodiesterase and mucosal cAMP accumulation. Cyclic AMP is thought to mediate small intestinal secretion caused by some enterotoxins, hormones, and methylxanthines. These studies were designed to evaluate the effect of caffeine on small intestinal net fluid movement and transit times. The administration of caffeine in amounts ordinarily contained in many beverages and medications (75 to 300 mg) resulted in striking net secretion in the jejunum which lasted at least 15 minutes. This occurred in six of seven studies. Baseline net absorption of 0.5 ml per cm per hr was reversed to net secretion of 6.0 +/- 2.2 ml per cm per hr after oral caffeine ingestion (P less than 0.01). Net secretion also occurred in the ileum in seven of eight studies, but the onset of secretion appeared 35 min later than in the jejunum. These patterns of secretion correlated best with the passage of the intestinal bolus of caffeine rather than plasma caffeine levels. In contrast to other net secretory conditions, which increase the speed of transit, small intestinal transit times, as determined by dye dilution methods, were unchanged by caffeine. It is possible that methylxanthine-induced small intestinal secretion may play a role in the symptoms experienced by some patients with functional diarrhea.     

First-pass metabolism of midazolam by the human intestine

The in vivo intestinal metabolism of the CYP3A probe midazolam to its principal metabolite, 1'-hydroxymidazolam, was investigated during surgery in 10 liver transplant recipients. After removal of the diseased liver, five subjects received 2 mg midazolam intraduodenally, and the other five received 1 mg midazolam intravenously. Simultaneous arterial and hepatic portal venous blood samples were collected during the anhepatic phase; collection of arterial samples continued after reperfusion of the donor liver. Midazolam, 1'-hydroxymidazolam, and 1'-hydroxymidazolam glucuronide were measured in plasma. A mass balance approach that considered the net change in midazolam (intravenously) or midazolam and 1'-hydroxymidazolam (intraduodenally) concentrations across the splanchnic vascular bed during the anhepatic phase was used to quantitate the intestinal extraction of midazolam after each route of administration. For the intraduodenal group, the mean fraction of the absorbed midazolam dose that was metabolized on transit through the intestinal mucosa was 0.43 +/- 0.18. For the intravenous group, the mean fraction of midazolam extracted from arterial blood and metabolized during each passage through the splanchnic vascular bed was 0.08 +/- 0.11. Although there was significant intersubject variability, the mean intravenous and intraduodenal extraction fractions were statistically different (p = 0.009). Collectively, these results show that the small intestine contributes significantly to the first-pass oxidative metabolism of midazolam catalyzed by mucosal CYP3A4 and suggest that significant first-pass metabolism may be a general phenomenon for all high-turnover CYP3A4 substrates.     

Response of human uterine arteries to local anesthetics

The in vitro effects of local anesthetics and norepinephrine upon strips of early gestation and term pregnancy uterine arteries were studied in eight cases. In another case, the effect upon uterine veins was studied with a standard organ bath used to record isometric contractions. Histologic preparations were made to verify the type of vessel studied. An artery obtained from an eight-week gestation did not respond to either lidocaine or mepivacaine. All other arterial specimens (radial and helicoidal strips) responded with slow, rising, strong contractions to diluted concentrations of both of these substances. Likewise they responded with rapid contractions when exposed to norepinephrine. Alpha blockers were unable to prevent the contractions triggered by the local anesthetics. The vein specimens did not respond to local anesthetics but contracted when stimulated by norepinephrine. Based on these observations and after brief review of some hypotheses advanced to explain post-paracervical anesthesia fetal bradycardia, it is postulated that this bradycardia is probably due to uterine artery spasm, causing decreased intervillous space blood flow and fetal hypoxia.     

Endocrine cells in the human fetal small intestine

In this report we describe the time of appearance and ultrastructural features of enteroendocrine (EECs) in the human fetal small intestine (SB) between 9 and 22 weeks gestation. Thirteen distinctive EECs were identified in fetal SB. Two of these, not found in normal adult SB, appeared within the stratified epithelium of the proximal SB at 9--10 weeks. They were arbitrarily termed "primitive" and "precursor" cells. As in all fetal EECs, the pale cytoplasm of the "primitive" cell contains a distinctive population of secretory granules (SGs). Primitive cell SGs average 200-330 nm; some have dense cores with lucent halos while others are filled with a homogeneous dense or flocculent material. The SGs of the "precursor" cells are larger, averaging up to 1 micron in diameter and their contents vary in electron density. A third group of cells not described in normal adult SB was arbitrarily termed "transitional" cells. These have two populations of SGs; one resembles the SGs of the "precursor" cells, and the other resembles the SGs of some of the specific adult type EECs. Transitional EC, S, I and G cells are seen. In addition, mature appearing EC, S, G, I, L, D, and D1 cells were identified by 12 weeks of gestation. The "primitive", "precursor", and "transitional" cells may represent sequential developmental precursors of adult type EECs.     

Ischaemia-reperfusion injury to the intestine

OBJECTIVES: To compare two programmes for reducing the levels of risk indicators of heart diseases among professional drivers. The programmes were focused on changes of lifestyle. The aim of the programmes was to initiate and motivate a process of change within the driver, which in the long term should lead to permanent and sound health habits. One programme was based on health profile assessment and the other was a health examination. METHODS: Altogether, 102 subjects were investigated (51 allocated to an intervention group and 51 to a reference group). The programme in the intervention group (health profile assessment) was based on revelatory communication, adjusted to the driver and contained individual and group activities. The reference group went through a health examination. In both groups blood pressure, serum lipid concentrations, body mass index, and estimated maximal oxygen uptake were measured and the lifestyle habits were surveyed by questionnaires at the start and at follow ups of 6 and 18 months. RESULTS: The results showed that in the intervention group the maximal oxygen uptake increased, as did exercise habits and the intention to practice good dietary habits. Variable working hours was the most common obstacle to change a health habit. In the reference group the maximal oxygen uptake increased and the concentration of serum total cholesterol and the number of people who perceived stress and loneliness decreased. CONCLUSIONS: Both the health profile assessment and the health examination had an effect on the levels of some risk indicators of heart diseases. Both programmes turned out to be useful because of high participation during the entire period and a generally positive attitude among the subjects.     

Regional redistributions of the blood in high and low small intestine obstruction

In the experimental model of high and low obstruction of the small intestine during 24 hours the authors observed considerable shifts in electrolytic blood content. Total amount of circulating blood, compared with control (laparotomy), was not changed. These data allowed a new consideration of the entity of the pathological syndrome in intestinal obstruction.     

The effects of large volume intravenous fluid infusion on neonatal renal function

Twenty healthy infants weighing less than 2,000 gm were studied at low (3.6 ml/kg/hr) or high (10.3 ml/kg/hr) rates of intravenous infusion. Inulin clearance determined by the constant infusion method was greater at the high rate of infusion (p = less than 0.05). Inulin clearance in two groups of infants over 2,000 gm studies at the same low or high rates of infusion did not increase at the higher rate of infusion. Since the GFR in infants less than 2,000 gm depends partially on the rate of intravenous infusion, small, healthy preterm infants may benefit from a rate of fluid administration greater than the low rate. When studies at low and high rates of infusion were compared in the 20 infants less than 2,000 gm, the fractional urinary sodium excretion increased with the increased fluid load. Delivery of fluid from the proximal tubule (CH2O =Na per dl GFR) increased (p less than 0.005). Free-water clearance and the absolute volume of urine increased at the high rate of infusion. These data indicate that the healthy preterm infant less than 2,000 gm, like the adult, compensates by increasing free-water clearance and urine volume when challenged with a large fluid load. Although fluid changes of short duration are appropriately handled, the effect of continuous rapid infusion on water and sodium balance in infants of this size remains to be determined.     

Response of human osteoblasts to implant materials: integrin-mediated adhesion

The initial interaction of the human osteoblast-like cell line Saos-2 with orthopaedic implant materials was analyzed to determine the mechanism by which these cells adhere to implant surfaces. Saos-2 cells were allowed to attach to disks composed of the orthopaedic implant materials Tivanium (Ti6A14V) and Zimaloy (CoCrMo) and to control disks of glass and plastic. Serum had no effect on the number of cells that attached to Tivanium and Zimaloy at 4 or 24 hours but did increase the number of cells that attached to glass at 24 hours. Collagen synthesis was determined by [3H]proline incorporation into collagenase-digestible protein and noncollagen protein. A significant increase of 19% was found for collagen synthesized in cells cultured on Zimaloy for 24 hours compared with glass, with no differences on Tivanium and plastic. However, collagenase-digestible protein and noncollagen protein were increased the most (204 and 198%, respectively) on Tivanium compared with glass. To determine if integrins were involved in cell attachment to implant materials, the peptide GRGDSP (Gly-Arg-Gly-Asp-Ser-Pro), which blocks integrin receptors through the Arg-Gly-Asp sequence, was added to the cells in serum-free medium. This peptide inhibited cell adhesion by 28% on Tivanium and 40% on Zimaloy but had no effect on glass and plastic. The control peptide GRADSP (Gly-Arg-Ala-Asp-Ser-Pro) had no effect on adhesion. Inhibition of protein synthesis and enzymatic removal of surface proteins did not affect the ability of Arg-Gly-Asp peptides to inhibit cell attachment to the implant materials. These results suggest that integrins are able to bind directly to Tivanium and Zimaloy. Western blot analysis of integrin protein demonstrated changes in many integrin subunits, depending on the substrate to which cells attached. In particular, the beta 1 integrin subunit was increased 3.8 to 9.5-fold at 24 hours. To determine specifically which integrins may be involved in adhesion, antibodies to integrins were added. An antibody to the fibronectin receptor, alpha 5 beta 1, significantly inhibited binding of cells to Tivanium by 63% and to Zimaloy by 49% and had no effect on glass. The vitronectin receptor antibody, alpha v beta 3/beta 5, did not alter cell adhesion. In conclusion, osteoblast-like cells appear to be capable of attaching directly to implant materials through integrins. The type of substrate determines which integrins and extracellular matrix proteins are expressed by osteoblasts. These data provide information on how implant materials may affect osteoblast differentiation and bone growth.     

Defining the critical limit of oxygen extraction in the human small intestine

Although animal models have been used to characterize the relation between oxygen consumption and blood flow, reliable data have not been generated in the human small intestine. We perfused segments of human small intestine by using an ex vivo perfusion circuit that allowed precise manipulation of blood flow and perfusion pressure. Our goal was to define the critical level of intestinal blood flow necessary to maintain the metabolic needs of the tissue. Human small intestine (n = 5) tissue obtained at transplantation harvest was transported on ice to the laboratory. A 40-cm mid-jejunal segment was selected for perfusion, and appropriate inflow and outflow vessels were identified and cannulated. Perfusion with an autologous blood solution was initiated through an extracorporeal membrane oxygenation circuit. After a 30-minute equilibration period, arterial and venous blood gases were measured at varying flow rates while maintaining a constant hematocrit level. Arterial and venous oxygen content, arteriovenous oxygen difference (A-VO2 diff), and oxygen consumption (VO2) were then calculated. Our results demonstrated that at blood flows > 30 ml/min/100 g, VO2 is independent of blood flow (1.6 +/- 0.06 ml/min/100 g), and oxygen extraction is inversely related to flow. Below this blood flow rate of 30 ml/min/100 g, oxygen extraction does not increase further (6.3 +/- 0.3 vol%), and VO2 becomes flow dependent. This ex vivo preparation defines for the first time a threshold value of blood flow for small intestine below which oxygen consumption decreases (30 ml/min/100 g). Previous animal studies have correlated such a decrease in oxygen consumption with functional and histologic evidence of tissue injury. This "critical" flow rate in human intestine is similar to that found previously in canine and feline intestine, but lower than that of rodent species.     

Nutritional aspects of dissimilatory sulfate reduction in the human large intestine

Physical pain is a major trigger for changes in many homeostatic systems of the body physiology. Our aim was to study the relationship between blood pressure, metabolism and pain perception in subjects with chronic pain symptoms. This was undertaken in a population-based study in primary health care, including subjects with widespread pain (n = 16), or localized pain (n = 15), and pain-free controls (n = 14). The main outcome measures were office and ambulatory blood pressure, glucose, insulin, lipids, and beta-endorphin. Subjects with widespread pain were more obese and showed higher levels than controls (p < 0.05) of fasting glucose (4.9 vs 4.5 mmol/l), cholesterol (6.9 vs 5.8 mmol/l) and office systolic blood pressure (133 vs 120 mmHg), while the subjects reporting localized pain had values in-between. Ambulatory blood pressure, insulin and beta-endorphin levels did not differ between the groups. In conclusion, subjects with widespread and/or intense chronic pain have higher BMI, more pronounced metabolic disturbances and higher (office) systolic blood pressure, but not ambulatory blood pressure, than subjects without chronic pain. Future epidemiological studies are needed to test whether this is compatible with increased cardiovascular risk.     

Technique for the continuous infusion of high doses of cocaine by osmotic minipump

The present article describes a procedure for modifying osmotic minipumps to avoid the local, toxic, necrotic effects of high concentrations of drug at the exit portal during the chronic, continuous infusion of cocaine. The present procedure eliminates the occurrence of necrotic skin lesions otherwise produced by SC administration of cocaine and/or other vasoconstrictive agents. The method of administration will therefore be useful for administration of other chronic drug regimens.     

Response to recombinant human erythropoietin in patients with myelodysplastic syndromes

OBJECTIVES: The impact of a positive surgical margin in otherwise confined prostate cancer after radical prostatectomy remains unclear. We analyzed the outcome of a large number of patients with organ-confined prostate cancer according to the presence and anatomic site of margin positivity. METHODS: We evaluated 2712 prostatectomy patients with Stage pT2N0 cancer (ie, no evidence of extra-prostatic disease, seminal vesicle or regional node involvement) and no prior therapy who were treated by radical prostatectomy between 1987 and 1995 at Mayo Clinic. A total of 697 patients (26%) had positive margins. To assess the effect of margin status in the absence of treatment, 378 patients with postoperative adjuvant therapy were not considered for the study group: the final group consisted of 2334 patients. RESULTS: Overall, 253 (58%) tumors were positive at the apex and/or urethra, 85 (19%) at the prostate base, 11 (2.5%) at the anterior prostate, and 174 (40%) at the posterior prostate; 89 (20%) had at least two margins involved and 21 (8.3%) had more than two involved. The apex/urethra was the only positive anatomic site in 183 (42%). Five-year survival free of clinical recurrence or prostate-specific antigen (PSA) biochemical failure (postoperative serum PSA of 0.2 ng/mL or more) for patients with a single positive margin was 79% for apex or urethra, 78% for anterior/posterior, and 56% for prostate base. Five-year survival free of clinical recurrence or PSA (biochemical) failure was slightly higher for those with one versus two margin-positive regions (77% versus 68%, respectively). Multivariate analysis revealed that positive surgical margins were a significant predictor of clinical recurrence and PSA (biochemical) failure (relative risk [95% confidence interval]: 1.65 [1.24, 2.18]) after controlling for Gleason grade, preoperative PSA, and deoxyribonucleic acid (DNA) ploidy. The effect of margin positivity on recurrence at a specific anatomic site (versus negative margins or positive at a different anatomic site) revealed the prostate base to be the only significant anatomic site when adjusted for grade, PSA, and ploidy. Five-year survival free of the combined clinical or PSA failure end point for those with versus those without positive margins at the prostate base was 56% versus 85%, respectively (P < 0.0001). CONCLUSIONS: Positive surgical margins are a significant predictor of recurrence in Stage pT2N0 cancer, which is independent of grade, PSA, and DNA ploidy. The impact of positive margin status on recurrence-free survival appears to be anatomic and site-specific, with prostate base positivity significantly associated with poor outcome. The benefit of adjuvant therapy based on anatomic site-specific margin positivity remains to be tested in order to optimize recurrence-free survival.     

Carbohydrate hydrolysis and absorption in the human small intestine in aging

Veterinary dental materials (e.g. documents, images, continuing education courses, message boards, bibliographic search options) that are available as electronic media are described. These include materials available on the Internet or via commercial on-line services such as AOL-VIN and Compuserve-NOAH, and off-line materials such as CD-i, CD-ROM and floppy disk programs.     

Starch utilization by Bacteroides ovatus isolated from the human large intestine

OBJECTIVE: It was hypothesized that there is an inverse relationship between resin-enamel bond strength and bonded cross-sectional area, and that there are regional differences in resin-enamel bond strength. METHODS: The facial and lingual surfaces of extracted human third molars were ground down 0.3 mm using 240 grit abrasive paper and were then bonded with either Clearfil Liner Bond 2 or Scotchbond Multi-Purpose Plus adhesive systems using the manufacturer's instructions. The bonded surfaces then received a resin composite build-up. After 24 h of storage in water, the bonded teeth were vertically serially sectioned into 1.0 mm thick slabs using a diamond saw, and the bonded surface area at the resin-enamel interface was varied from 0.5 to 3.0 mm2 using a diamond saw under microscopic observation. The trimmed region was varied from the occlusal third of the facial or lingual enamel to the middle third, to the cervical third. The trimmed specimens were then glued to a Bencor Multi-T device, placed in an Instron testing machine and stressed to failure at 1 mm/min. A three-factor ANOVA was used to compare bond strengths (buccal vs. lingual, occlusal vs. middle vs. cervical-third, vs. materials). Regression analysis was used to examine the relationship between bond strength and bonded cross-sectional area for each material on occlusal enamel. RESULTS: For both bonding systems, there was a highly significant (p < 0.001) inverse exponential relationship between tensile bond strength (y axis) and bonded cross-sectional area (x axis) with y intercepts of 51 and 59 MPa for Clearfill Liner Bond 2 and Multi-Purpose Plus, respectively. Using both materials, the highest bond strengths were measured in the occlusal third, which were significantly higher (p < 0.05) than those made to cervical enamel. SIGNIFICANCE: Like resin-dentin bonds, resin-enamel bonds exhibit an inverse relationship with cross-sectional area. This relationship becomes more apparent at bonded surface areas below 2 mm2 and is probably due to reductions in the number of interfacial stress-raisers as samples are made smaller.     

Time-dependent pharmacokinetics of high dose thiopental infusion in intensive care patients

PURPOSE: In patients with severe head injuries receiving long-term infusion for reducing intracranial pressure, a decline in concentrations was apparent following attainment of an initial steady state. This could be explained by an increased rate of elimination. An adequate modeling of the plasma disposition curves was used to demonstrate clearly the metabolic induction. METHODS: The concentration-time data of 17 patients were fit by a one compartment pharmacokinetic model in which the decline of plasma concentration during infusion was due to an increase in the clearance rate of thiopental following a latency period. This time-dependent clearance model provided estimates of initial and final clearance rates. RESULTS: This study demonstrated that large interindividual variations were observed during the course of the thiopental time-dependent pharmacokinetics. Depending on the patient, one or two steps of induction occurred. The mean initial and final clearance rates were 1.22 +/- 0.82 mL/min/kg and 10.5 +/- 23 mL/min/kg. The latency period for the first induction averaged 69 +/- 56 h. For 6 subjects, the rate of thiopental metabolism continued to change with time and there was a second step of induction. CONCLUSIONS: Induction of thiopental metabolism occur within therapeutic ranges, but it was not established that attainment of individual limits in dosing rate, total dose, or treatment duration occur in the process. Thus, monitoring is needed for achievement of a target plasma concentration.     

Intracoronary infusion of reduced glutathione improves endothelial vasomotor response to acetylcholine in human coronary circulation

BACKGROUND: Oxygen free radicals have been shown to cause endothelial vasomotor dysfunction. This study examined the effect of reduced glutathione (GSH), an antioxidant, on human coronary circulation. METHODS AND RESULTS: Responses of epicardial diameter and blood flow of the left anterior descending coronary artery to intracoronary infusion of acetylcholine (ACh, 50 microg/min) were measured by quantitative coronary angiography and Doppler flow-wire technique, respectively, before and during combined intracoronary infusion of GSH (50 mg/min) or saline in 26 subjects with no significant coronary stenosis. GSH infusion suppressed the constrictor response of epicardial diameter to ACh and enhanced the increase in blood flow response to ACh. Furthermore, GSH potentiated the coronary dilator effect of nitroglycerin. A beneficial effect of GSH on the epicardial diameter response to ACh was observed in a subgroup of subjects with > or = 1 coronary risk factors but not in a subgroup without risk factors. Saline infusion did not have any effects. CONCLUSIONS: The results indicate that GSH improved coronary endothelial vasomotor function, particularly in subjects with coronary risk factors, and it potentiated the vasodilator effect of nitroglycerin in human coronary arteries.     

Aspiration to obtain osteoblast progenitor cells from human bone marrow: the influence of aspiration volume

Bone marrow contains osteoblast progenitor cells that can be obtained with aspiration and appear to arise from a population of pluripotential connective-tissue stem cells. When cultured in vitro under conditions that promote an osteoblastic phenotype, osteoblast progenitor cells proliferate to form colonies of cells that express alkaline phosphatase and, subsequently, a mature osteoblastic phenotype. We evaluated the number of nucleated cells in bone-marrow samples obtained with aspiration from the anterior iliac crest of thirty-two patients without systemic disease. There were nineteen male patients and thirteen female patients; the mean age was forty-one years (range, fourteen to seventy-seven years). The prevalence and concentration of the osteoblast progenitor cells also were determined, by placing the bone-marrow-derived cells into tissue-culture medium and counting the number of alkaline phosphatase-positive colony-forming units. In order to assess the effect of aspiration volume, two sequential experiments were performed. In the first experiment, aspiration volumes of one and two milliliters were compared. In the second experiment, aspiration volumes of two and four milliliters were compared. The mean prevalence of alkaline phosphatase-positive colony-forming units in the bone-marrow samples was thirty-six per one million nucleated cells (95 per cent confidence interval, 28 to 47); a mean of 2400 alkaline phosphatase-positive colony-forming units was obtained from a two-milliliter aspirate. There was a significant difference among the patients with respect to the number of alkaline phosphatase-positive colony-forming units in these bone-marrow samples (p < 0.001). Seventy per cent of this variation in the prevalence was due to variation among patients, and 20 per cent was due to variation among aspirates. The number of alkaline phosphatase-positive colony-forming units in the aspirate increased as the aspiration volume increased. However, contamination by peripheral blood also increased as the aspiration volume increased. An increase in the aspiration volume from one to four milliliters caused a decrease of approximately 50 per cent in the final concentration of alkaline phosphatase-positive colony-forming units in an average sample. CLINICAL RELEVANCE: On the basis of these data, we recommend that, when bone marrow is obtained with aspiration for use as a bone graft, the volume of aspiration from any one site should not be greater than two milliliters. A larger volume decreases the concentration of osteoblast progenitor cells because of dilution of the bone-marrow sample with peripheral blood. We estimate that four one-milliliter aspirates will provide almost twice the number of alkaline phosphatase-positive colony-forming units as will one four-milliliter aspirate. In addition, these data confirm that humans differ significantly from one another with respect to the cellularity of bone marrow and the prevalence of osteoblast progenitor cells. Additional studies are necessary to determine if the number or prevalence of alkaline phosphatase-positive colony-forming units in bone marrow is a determining factor in the efficacy of an autogenous bone or bone-marrow graft and to ascertain how the number and function of alkaline phosphatase-positive colony-forming units may change as a function of factors such as age, menopausal status, and selected diseases.