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Biomedical subjects

A B Thomson

Publications and source records attributed to A B Thomson.

At least 307 records · Page 17Linked to original sources
PubMed1982

Diffusion barriers to passive lipid uptake of canine posterior tracheal epithelium.

In studies of passive uptake of canine posterior tracheal epithelium in vitro, we examined the effective resistance of the unstirred water layer (UWL) when the bulk phase of the preparation was stirred and unstirred. Rates of uptake of fatty acids were corrected for unstirred layer effects. The incremental change in free energy, derived from the linear relationship between uptake and chain length of lipids, was -271 cal/mol. Measurement of the effective thickness (d) and surface area (SW) of the UWL showed that d fell and SW rose as the rate of stirring increased. SW was less than 15% of the tracheal epithelial cell membrane's surface area. It is concluded that 1) lipid membrane of the tracheal epithelium and the overlying UWL represent the major diffusion barriers for lipid uptake across the tracheal epithelium; 2) failure to correct for the UWL resistance leads to serious errors in the estimates of permeability properties of the epithelium to lipids; and 3) the unstirred layer severely limits the proportion of cell membrane available for transport in vitro.

Animals↗
PubMed1982

Pathophysiologic and ultrastructural basis for intestinal symptoms in Fabry's disease.

Fabry's disease is a rare, sex-linked disorder of glycolipid metabolism. We describe a patient with watery diarrhea, early satiety, and asymptomatic cholelithiasis. The jejunal aspirate demonstrated bacterial overgrowth; sigmoidoscopy showed rectal angiokeratoma corpora diffusum. The gastric emptying rate measured with 99mTc-sulfur colloid was markedly prolonged and the fasting gastrin was elevated at 276 pg/ml. The (14C)glycocholate breath test demonstrated a markedly elevated peak at 4 h, associated with an increased fecal bile acid loss of 0.82 g/day. Oral cholecystogram showed a solitary radiolucent stone in a functioning gallbladder. The bile acid pool size and lithogenic index were normal. Light microscopy of small bowel and rectal biopsy specimens revealed normal surface epithelium, but enlarged and vacuolated ganglion cells in Meissner's plexus. Electron microscopy showed laminated and amorphous osmiophilic deposits within ganglion cells of the submucosal plexus, within smooth muscle cells of the muscularis mucosae, and within endothelial cells lining arterioles, venules, and capillaries, but not in autonomic nerve fibers or enterocytes. The diarrhea and early satiety responded promptly to metoclopramide and to tetracycline. The early satiety was likely on the basis of delayed gastric emptying due to deposition of sphingolipid within ganglion cells of the autonomic nervous system; the diarrhea was likely on the basis of intestinal stasis with bacterial overgrowth and bile salt wastage.

Adult↗
PubMed1981

Aging and cholesterol uptake in the rabbit jejunum: role of the bile salt micelle and the unstirred water layer.

A previously validated in vitro technique was used to determine the effect of aging upon the rate of uptake of cholesterol into the jejunum of suckling, young, and older rabbits. Cholesterol uptake was greater in suckling than in older animals, over a wide range of durations of incubation and varying concentrations of cholesterol or bile acid. The rate of uptake of cholesterol in the young animals was intermediate between the values seen in the suckling and older rabbits. This greater uptake of cholesterol in the younger than in the older animals persisted when the effective resistance of the unstirred water layer (UWL) was varied by stirring the bulk phase. In contrast, the uptake of medium- and long-chain length fatty acids was greater in the young than in the older animals when UWL was low, but the converse was true when UWL was high at each rate of stirring of the bulk phase. The UWL was lower in the younger than in the older rabbits. Thus, the differences in the in vitro uptake of cholesterol into the jejunum of rabbits of varying age is due to the greater passive permeability properties and greater functional membrane surface area of the jejunum of young animals, and the lower effective resistance of the overlying unstirred water layer.

Aging↗
PubMed1981

Intestinal cholesterol uptake from phospholipid vesicles and from simple and mixed micelles.

This study was undertaken in vitro to examine the rat jejunal uptake of cholesterol from phospholipid vesicles and from mixed bile salt micelles, under conditions of low effective resistance of the intestinal unstirred water layer. Cholesterol uptake, Jd, occurred from vesicles only when the cholesterol:phospholipid ratio was high. The addition of phospholipid (PL) to micelles comprising 20 mM taurodeoxycholic acid (TDC) extended the concentration of cholesterol, beyond which the relationship between cholesterol concentration and uptake remained linear. When the concentration of cholesterol in the bulk phase was held constant and the concentration of TDC or of PL added to the TDC was increased, there was a decline in cholesterol uptake; this effect was masked when the concentration of TDC was high, or when higher concentrations of PL were added to the mixed micelle. When increasing concentrations of palmitic acid were added to mixed micelles composed of cholesterol, TDC and PL, the uptake of cholesterol decreased; in contrast, cholesterol uptake progressively increased when palmitic acid was added to simple TDC micelles. The results suggest that the mechanism responsible for cholesterol uptake may vary, depending on the nature of the constituents of the micelle, and it is proposed that PL inhibits the intestinal uptake of cholesterol by altering the partitioning of cholesterol out of the micelle.

Animals↗
PubMed1981

A theoretical discussion of the use of the Lineweaver-Burk plot to estimate kinetic parameters of intestinal transport in the presence of unstirred water layers.

Transport of a solute molecule from the bulk phase in the intestinal lumen into the mucosal cells is determined by the rate of movement of the solute molecule across two barriers, the unstirred water layers (UWL) and the microvillus membrane. Failure to account for the effect of the resistance offered by the UWL introduces significant errors into the estimate of kinetic constants of carrier-mediated transport, and these errors may be further magnified by the use of the Lineweaver-Burk plot. This study was under taken to determine use of this plot under conditions that depict the effect of varying the effective resistance of the UWL, the distribution of transport sites along the villus (fn), the passive permeability coefficient (P), the maximal transport rate (Jdm), and the Michaelis constant (Km). Theoretical curves derived from a new equation demonstrate that (1) the Lineweaver-Burk plot is linear under only a limited number of conditions, and even then may lead to serous over- or under-estimation of Jdm and Km; (2) failure to correct for passive permeation may give rise to additional quantitative discrepancies between the true and apparent values of Jdm and Km; and (3) the qualitative characteristics of a carrier-mediated intestinal transport system may be ascertained only after correction for the contribution of passive permeation, and after correction for the effective resistance of the UWL.

Biological Transport↗
PubMed1981

Uptake of cholesterol into rabbit jejunum using three in vitro techniques: importance of bile acid micelles and unstirred layer resistance.

The rate of uptake (Jd) of cholesterol into the intestine is influenced by the effective resistance of the unstirred water layer, the concentration of the probe molecule at the aqueous-membrane interface, and the passive permeability characteristics of the membrane. This study was undertaken to determine the influence of the bile acid micelle and the unstirred water layer on the Jd of cholesterol into rabbit jejunum, using everted sacs, full-thickness biopsies, and disks. When the bulk phase was stirred and the resistance of the unstirred layer was low, there was a linear relation between cholesterol concentration in the bulk phase and Jd when the concentration of taurodeoxycholic acid (TDC) was constant, but increasing TDC in the presence of a constant concentration of cholesterol was associated with a decline in Jd. When the concentration of both TDC and cholesterol was varied but the ratio of TDC to cholesterol was maintained constant, Jd increased slightly. The Jd of cholesterol was higher into sacs than into biopsies, which in turn was greater than into disks; Jd into disks was much lower when the resistance of the unstirred layer was high. These results suggest that 1) the bile acid micelle serves to provide a reservoir for partitioning of the cholesterol from the micelle into the aqueous phase from which the cholesterol is absorbed; 2) the Jd of cholesterol into disks of jejunum is influenced by the effective resistance of the unstirred water layer; and 3) although the quantity of cholesterol Jd varies markedly between sacs, biopsies, and disks, the qualitative aspects of the role of the bile acid micelle in cholesterol absorption were similar using the different in vitro techniques.

Animals↗
PubMed1981

Uptake of glucose into the intestine of diabetic rats: effects of variations in the effective resistance of the unstirred water layer.

Diabetes mellitus in rats is associated with enhanced intestinal absorption of glucose, but the kinetic basis for this observation is disputed. Only recently has it been appreciated that failure to account for the resistance of the unstirred water layer (UWL) leads to gross errors in the estimation of the kinetics of active and passive transport. Accordingly, the uptake Jd (unidirectional flux rate) of glucose into the intestine was measured in alloxan- or streptozotocin-diabetic rats (DM) and in control animals (C) under conditions selected to yield low and high UWL resistance. When the UWL resistance was minimized by stirring the bulk phase, Jd was higher in DM than in C, but only from the higher concentrations of glucose; this difference between DM and C was obscured when UWL was high. The difference between C and DM in Jd from 40 mM glucose progressively increased from 3 to 83 days after induction of DM, and was present in the jejunum and ileum as well as in young and old animals. The Jd from 0.5 to 2 mM glucose was similar in DM and C, and the inhibitory effect of galactose on Jd of glucose was similar in DM and C. Jd was higher in DM than in C for L-glucose and for D-glucose in the presence of phlorizin and in the absence of sodium ion. Kinetic analysis demonstrated a higher maximal transport rate (Jdm) and apparent passive permeability coefficient (P*) in DM than in C, but the apparent affinity constant was unchanged. It is concluded that (1) the greater Jd of glucose in DM is due to a greater Jdm and P*, rather than due to changes in the properties of the glucose carrier itself, and (2) these differences may be obscured by variations in UWL.

Animals↗
PubMed1980

Passage of iron out of the intestinal mucosa of the rat.

To determine the effect of removal of the "lumen-to-mucosa" concentration gradient on the passage of iron (Fe) out of the intestine, duodenal loops of rats with loaded (FeL) or deficient (FeD) iron stores were perfused for 30 min with 5.0 mM solutions containing 59Fe. The test solutions were then removed and in vivo perfusion of the washed mucosa was continued for up to 60 min with saline or unlabelled FE-saline. Despite the greater initial uptake of Fe by FeD than FeL, continued perfusion with saline was associated with the appearance of similar quantities of 59Fe in the perfusate; in contrast, when perfusion was continued with Fe-saline, the loss of 59Fe into the perfusate was increased and was twice as great in FeD as in FeL. Iron transfer to the carcass was higher in FeD than in FeL, but continued perfusion with saline was associated with the appearance of increased amounts of 59Fe in the carcass of FeL but not FeD; the amount of 59Fe appearing in the carcass was greatly increased in both FeD and FeL by continued perfusion with Fe-saline. Thus, the amount of 59Fe available for entry into the intestinal lumen and carcass after removal of the lumen-to-mucosa concentration gradient is influenced by the size of the body iron stores and by the presence of iron in the fluid remaining in the lumen. Therefore, the amount of iron in the fluid remaining in the intestinal lumen after the administration of the Fe test dose must be carefully defined when estimating the kinetics of the intestinal absorption of iron.

Animals↗
PubMed1980

Effect of age on uptake of homologous series of saturated fatty acids into rabbit jejunum.

The effect of age on the rate of uptake (Jd) of a homologous series of saturated fatty acids into rabbit jejunum was determined in suckling, mature, and old animals. A previously validated in vitro technique was used, and the bulk phase was stirred at different rates to vary the effective resistance of the unstirred water layer (UWL). When UWL was high, Jd of fatty acids was greater in old than in young animals; Jd was greatly increased when UWL was low, and Jd was not higher in the suckling and mature rather than the old animals. At each rate of stirring UWL was lowest in the suckling rabbits and highest in the old animals. The values of Jd were corrected for UWL, yielding estimates of the true passive permeability properties of the membrane. From these values, the incremental free energy change associated with the addition of each -CH2- group to the fatty acid chain was 50% higher in the suckling and mature animals than in the old animals, and the estimated surface area of the jejunal membrane was also higher in the suckling and mature animals. Variations in UWL had a profound effect on the Jd of passively absorbed fatty acids, and failure to account for UWL leads to gross underestimation of the permeability properties of the jejunal microvillus membrane. Furthermore, the difference between the true and apparent passive permeability coefficients becomes greater as the fatty acid chain length increases. The results suggest that discrepancies in uptake of fatty acids in animals of different ages are explained by differences in the passive permeability properties and functional surface area of the membrane and by differences in the overlying UWL.

Aging↗
PubMed1980

Intestinal kinetic parameters: effects of unstirred layers and transport preparation.

Three in vitro tissue preparations were used to derive kinetic parameters for the transport of D-glucose in rabbit jejunum, and the resistance of the unstirred water layer was varied by altering the rate of stirring of the bulk phase. The apparent permeability coefficient (Pd*) of the rabbit jejunum for D-glucose was much higher from everted sacs and full-thickness biopsies than from intestinal discs. Failure to adjust the experimentally determined flux for the contribution of the passive component led to errors in the estimation of the maximal transport rate (Jdm) and in the apparent Michaelis constant (Km*). Jdm was higher in biopsies than everted sacs or discs, Km was also higher in biopsies. With each tissue preparation Km* and Pd* were markedly influenced by stirring the bulk phase, whereas Jdm was unchanged. The results indicate that failure to account for the effect of the passive component and the unstirred layer leads to major errors in the estimation of Km*, Pd*, and Jdm. Furthermore, the magnitude of these kinetic constants is influenced by the type of in vitro system used to derive the constants, and it is therefore invalid to extrapolate the results obtained using one preparation to those utilizing another preparation, or to the in vivo situation.

Animals↗
PubMed1980

Unidirectional flux rate of cholesterol and fatty acids into the intestine of rats with drug-induced diabetes mellitus: effect of variations in the effective resistance of the unstirred water layer and the bile acid micelle.

A previously validated in vitro technique was used to study the unidirectional flux rate (Jd) of cholesterol and a homologous series of saturated fatty acids (FA) into the jejunum and ileum of rats and alloxan or streptozotocin-induced diabetes mellitus (DM), under conditions of variable resistance of the intestinal unstirred water layer (UWL), and under conditions of varying concentrations of taurodeoxycholic acid (TDC). When the bulk phase was stirred and UWL was low, th Jd of FA 2:0, 4:0, 10:0, and 12:0 were greater in the jejunum and ileum of DM than controls, both 3 and 14 days after alloxan or streptozotocin; the incremental free energy change of transfer of FA was thus higher in DM. The Jd of FA 16:0, 18:0, and cholesterol were increased at 14 but not 3 days after induction of DM; the Jd of cholesterol was higher in DM over a wide range of concentrations of cholesterol, TDC, and both cholesterol and TDC. The Jd of all probe molecules was lower when the bulk phase was unstirred and UWL was high; the Jd of cholesterol but not FA remained greater in DM than in controls. The results suggest that a) the passive permeability of the diabetic intestine to fatty acids is increased in DM but this difference is lost as the animals age; b) the Jd of cholesterol is greater in the jejunum and ileum in DM under conditions of variable concentrations of both cholesterol and bile acids; and c) the bile salt micelle functions in both DM and in controls to solubilize cholesterol and provide the source from which the cholesterol partitions prior to its uptake by the intestinal mucosal membrane.

Animals↗
PubMed1980

Influence of site and unstirred layers on the rate of uptake of cholesterol and fatty acids into rabbit intestine.

Passive permeation into the intestine is influenced by resistance of the unstirred water layer (UWL) and the microvillus membrane. Failure to account for UWL leads to gross underestimation of apparent passive permeability coefficients, and to qualitative errors in the interpretation of the nature of absorptive processes. A previously validated in vitro technique was used 1) to determine the permeability characteristics of the rabbit jejunum (J) and ileum (I) towards a homologous series of saturated fatty acids; 2) to measure UWL in jejunum and ileum under conditions of variable effective resistance of the UWL; and 3) to estimate the preferential site of absorption of cholesterol in the intestine. The rate of uptake, Jd, of fatty acids was similar in J and I when UWL was high; although Jd was higher in J than I when UWL was low, the UWL was smaller in I than J at each rate of stirring of the bulk phase, and the incremental free energy change for the uptake of medium chain-length fatty acids was similar in J and I, indicating similar passive permeability characteristics along the length of the intestine. However, the intercept of the relationship between chain length and uptake was significantly different for the two sites, suggesting a greater surface area, Sm, of the membrane in J than I. These findings persisted over a wide range of different periods of incubation and of concentrations of cholesterol and bile acids. The results suggest that i) cholesterol uptake in the J and I occurs from an aqueous monomolecular phase into the microvillus membrane; and ii) reported variations in the Jd of cholesterol along the intestine are likely due to differences in UWL, Sm, or availability of substrate and not to differences in the permeability properties of the intestine.

Animals↗
PubMed1979

Kinetic constants for intestinal transport of four monosaccharides determined under conditions of variable effective resistance of the unstirred water layer.

Theoretical considerations have suggested that variations in the resistance of the unstirred water layer (UWL) have a profound effect on the kinetic constants of intestinal transport. In this study, a previously validated in vitro technique was employed to determine the unidirectional flux rate of glucose, galactose, 3-O-methyl glucose and fructose into the rabbit jejunum under carefully-defined conditions of stirring of the bulk phase known to yield different values for the effective resistance of the UWL. For each monosaccharide, uptake is much greater when the resistance of the UWL is low than when high. The maximal transport rate, Jd m, of glucose was half as large as the Jd m of galactose and 3-O-methyl glucose (3-O-MG), and was twice as great as the Jd m of fructose. The apparent affinity constant, Km * of glucose is less than that of fructose, which was lower than the Km * of galactose and 3-O-MG. The use of the Lineweaver-Burk double reciprocal plot is associated with an overestimation of both Jd m and Km *. This discrepancy between the true and apparent values of the kinetic constants is much greater for lower than for higher values of Jd m and Km *; variations in the resistance of the unstirred layer influences the magnitude and direction of the discrepancy. The apparent passive permeability coefficient is similar for each sugar, but because of the different values of Jd m, passive permeation contributes relatively more to the uptake of glucose and fructose than of galactose or 3-O-MG. Under conditions of high unstirred layer resistance, differences in uptake rates of the sugars are due to differences in their Jd m rather than their Km *. Kinetic analysis is compatible with the suggestion that the glucose carriers are predominantly near the tip of the villus, whereas those for galactose and 3-O-MG are located along the entire villus and the Km * of their carriers at the tip is lower than their Km * towards the base of the villus. It is proposed that there are multiple or heterogeneous intestinal carriers for glucose, galactose and 3-O-methyl glucose in the jejunum of the rabbit.

Animals↗
PubMed1979

Limitations of the Eadie-Hofstee plot to estimate kinetic parameters of intestinal transport in the presence of an unstirred water layer.

In the presence of an intestinal unstirred water layer, the relationship between substrate concentration (C1) and unidirectional flux (Jd) is not described by the equation for a rectangular hyperbole. Accordingly, transformations of the Michaelis-Menten equation may not necessarily be linear and may lead to serious errors in the estimation of the affinity constant (Km) and maximal transport rate (Jdm) of carrier-mediated processes. An equation has previously been derived which described Jd under conditions of varying effective thickness or surface area of the unstirred water layer, the free diffusion coefficient of the probe molecule, and the distribution of transport sites along the villus. These theoretical curves have been analyzed by using the Eadie-Hofstee transformation (Jd vs. Jd/C1) of the Michaelis-Menten equation. Use of this plot leads to serious discrepancies between the true and apparent affinity constants and between true and apparent maximal transport rates. These differences are further magnified by failure to correct for the contribution of passive permeation. The Eadie-Hofstee plot is of use, however, to infer certain qualitative characteristics of active transport processes, such as the variation in affinity constants and overlying resistance of the unstirred water layer at different sites along the villus and to predict the adequacy of the correction for the contribution of passive permeation.

Animals↗
PubMed1979

Transport kinetics of D-glucose in human small intestinal mucosa: rate constants in histologically normal and abnormal mucosal biopsies.

Using D-glucose as the probe molecule, we analysed conditions which must be fulfilled in mucosal biopsy studies before the kinetic nature of the transport process can be established. Mucosal biopsies were obtained from the region of the ligament of Treitz from four healthy volunteers and from 47 patients: 29 of the 47 had histologically normal mucosa; seven had mild abnormalities; and 11 had moderate or severe ("flat") abnormalities in villus architecture. The rate of uptake of 40 mM glucose was constant only between 4 and 10 min, extrapolating through zero uptake at zero time with a constant adherent mucosal fluid volume. Incubation for shorter or longer periods was associated with over- or underestimation of the rate of uptake. Failure to use a nonabsorbable marker was also associated with overestimation of the rate of uptake. When biopsies were incubated for 6 min, a curvilinear relationship was observed between uptake rate and concentration. In biopsies with moderate and severe abnormalities, there was a marked reduction in the magnitude of the maximal transport rate and the apparent passive permeability coefficient, with little change in the magnitude of the apparent affinity constant. When human mucosal biopsies are used to study nutrient absorption, certain criteria must be fulfilled to establish valid rate constants and to make comparisons between normal and abnormal mucosa.

Adolescent↗