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Immunoreactive insulin, like inulin, quickly equilibrates with interstitial fluid, as evidenced by recovery in thoracic duct lymph in man. Insulin-like activity not accounted for by immunoreactive insulin behaves as a large protein and is confined to the vascular compartment.
BACKGROUND: Pathogenesis of inflammatory bowel disease is thought to be through different factors and there is a relationship between the gut flora and the risk of its development. Probiotics can manipulate the microflora in chronic inflammation and may be effective in treating inflammation. Bifidobacterium are saccharolytic and their growth in the gut can be promoted by non-absorbable carbohydrates and its increase in the colon appears to be of benefit. METHODS: Oligofructose and inulin (OFI) alone and the two B. infantis DSM 15158 and DSM 15159 with and without OFI, were fed to Sprague-Dawley rats for 7 days prior to colitis induction and administrations continued for another 7 days with the DSS. Colitis severity assessed using a Disease Activity Index. Samples were collected 7 days after colitis induction, for intestinal bacterial flora, bacterial translocation, short chain fatty acids (SCFAs), myeloperoxidase (MPO), cytokines (IL-1beta, TNF-alpha, IL-10 and TGF-beta) and malondialdehyde (MDA). RESULTS: OFI alone or the B. infantis strains with and without OFI improved significantly the DAI and decreased colonic MPO activity. Colonic tissue IL-1beta decreased significantly in all treated groups except B. infantis DSM 15158. MDA decreased significantly in B. infantis DSM 15159 with and without OFI compared to colitis control. Succinic acid increased significantly in OFI group with and without DSM 15159 compared to all groups. Sum values of propionic, succinic acid and butyric acid increased significantly in all groups compare to the colitis control. Bacterial translocation to mesenteric lymph nodes decreased significantly in all groups compared to colitis control. Translocation to the liver decreased significantly in all groups compare to the colitis control and OFI + B. infantis DSM 15158 groups. CONCLUSION: Administrations of OFI and Bifidobacterium improve DSS-induced acute colitis and have an anti-inflammatory effect. Major differences in effect were observed between the two B. infantis strains as indicated in MDA and succinic acid concentration as well as bacterial translocation rate in synbiotic combinations.
BACKGROUND: It is generally assumed that the tissue exchange of antibiotics is flow limited (complete equilibration between the capillary and the tissue water). This assumption may not be valid if there is a large amount of plasma protein binding because the effective capillary permeability depends on the product of the intrinsic capillary permeability (PS) and the fraction of solute that is free in the blood (fwB). PKQuest, a new generic physiologically based pharmacokinetic software routine (PBPK), provides a novel approach to modeling capillary permeability in which the only adjustable parameter is the PS of muscle. METHODS: All the results were obtained by applying PKQuest to previously published human pharmacokinetic data. RESULTS: The PKQuest analysis suggests that the highly protein bound antibiotics dicloxacillin and ceftriaxone have a significant capillary permeability limitation. The human muscle capillary PS of inulin, dicloxacillin and ceftriaxone was 0.6, 13 and 6 ml/min/100 gm, respectively. The ceftriaxone protein binding is non-linear, saturating at high plasma concentrations. The experimental ceftriaxone data over a wide range of intravenous inputs (0.15 to 3 gms) was well described by PKQuest. PKQuest is the first PBPK that includes both permeability limitation and non-linear binding. CONCLUSIONS: Because of their high degree of plasma protein binding, dicloxacillin and ceftriaxone appear to have a diffusion limited exchange rate between the blood and tissue and are not flow limited as had been previously assumed. PKQuest and all the examples are freely available at http:\\www.pkquest.com.
Thirty-eight healthy newborn infants with gestational ages ranging from 25 to 42 weeks were studied at 2 days to 9 weeks postnatal age to evaluate the rate of glomerular maturation after birth. Glomerular function was assessed by a constant infusion method for inulin clearance (Cin). Cin was nearly identical when measured by the traditional clearance method and by the constant infusion technique. The Cin of 22 infants 2-3 days old ranged from 0.6 to 17.9 ml/min and was directly related to gestational age (r = 0.81, P less than 0.001). For 26 infants studied at 1-9 weeks of age, Cin was directly proportional to conceptual (gestational and postnatal) age (r = 0.89, P less than 0.001), and approximated that of infants of similar gestational age studied at 2-3 days of age.
Measurement of the water content and inulin space of the tissues of the ampulla, ampullary-isthmic junction and proximal isthmus showed that the loss of oedema was related to the position of the ova, whether this was normal (after hCG), delayed (by oestrogen treatment) or accelerated (by progesterone treatment).
The suitability of utilizing 125-I-iothalamate to estimate the volume of extracellular fluid was assessed in ureterally ligated chickens. Subsequent to intravenous administration the movement of labeled iothalamate from the plasma compartment follows closed two-compartment kinetics and equilibration between vascular and extravascular phases is attained in about 20 minutes. The volume of distribution of 125-I-iothalamate prior to and following the influsion of 0.15 M NaCl (equal to 15% of the estimated ECFV) averaged 23.6 plus or minus 0.61 and 28.4 plus or minus 0.22% of the body weight, respectively. The observed postsaline labeled iothalamate space did not differ statistically from the expected value. When administered simultaneously inulin penetrates into an apparent volume that is 75% of the labeled iothalamate space after 60 minutes. The content of 125-I-iothalamate is relatively high in liver and kidney tissue and suggests that these are major sites where removal of the indicator from plasma occur. It is suggested that 125-I-iothalamate, under appropriate conditions, could be used to measure the plasma volume and the extravascular fluid with which plasma is in rapid diffusion equilibrium.
A peer-verified, gas chromatographic (GC) method is presented for the identification of hydrolyzed inulin syrup (HIS) and high-fructose corn syrup (HFCS) in apple juice. The procedure involves determining the Brix value of the apple juice or apple juice concentrate and preparing a dilution of the test sample to 5.5 degrees Brix. A 100 microL aliquot of the 5.5 degrees Brix test solution is then freeze-dried in a GC autosampler vial. The sugars in the freeze-dried residue are converted to trimethylsilyl derivatives, by the addition of an appropriate silylation reagent, and the vial is heated at 75 degrees C for 30 min. After derivatization, the solution is introduced into a gas chromatograph where the analytes are separated on a 30 m, 0.25 mm id DB-5 column. The method can use hydrogen, helium, or nitrogen as the carrier gas. The analytes and marker compounds are measured by use of a flame ionization detecone of the 2 syrups at 2 levels. Dilution was ascertained by the presence of retrograde sugar markers found in the 2 sugar syrups. All 3 laboratories involved in the study were able to identify the correct diluent in the blind, randomly coded, apple juice test portions. The levels of dilution in the test portions were 0, 6.9% (HIS), 16.0% (HIS), 8.1% (HFCS), and 17.0% (HFCS). No false positive results were reported. Quantitative conclusions can be drawn when the same syrup is used for dilution and as a reference standard.
On account of the solution of the problem, whether already after a four weeks' therapy with antibiotics in chronic progressing pyelonephritis a measurable increase of function may develop, the combined PAH-inulin-clearance was performed 35 times. 9 patients did not show a clear restriction of the clearance, wherefore in these cases a control examination was not necessary. In 10 patients of 12 an increase was present, in 7 patients a significant increase of the renal function existed after the therapy carried out. Therefore already after antibiotic impact therapy in patients with chronic pyelonephritis without provable acute episode an improvement of the function can occur, which is to be increased or kept by means of the long-term treatment.
Cyclic AMP has been generally recognised as activator of cAMP-dependent protein kinases. However, there is little evidence about role of cAMP-dependent protein kinase (PKA), in particular izoenzymes PKA-I and PKA-II, in glomeruli contractility. We measured changes of glomerular inulin space (GIS) as a marker of its contractility in the presence of phosphodiesterase resistance cAMP analogues; activators and inhibitors of PKA. Activator of PKA i.e. (Sp) 8-Cl-cAMPS (0.1-100 microM) decreased GIS. (Rp) 8-Cl-cAMPS (0.1-100 microM), inhibitor of PKA, was ineffective but shifted concentration-response curve of (Sp) 8-Cl-cAMPS to right at 50 microM. Specific A site activation by N6-benzoyl-cAMP decreased GIS with maximum at 0.1 microM. Activation of B site by 8-aminobutyloamino-cAMP (0.1-100 microM) had no effect. However, specific activation of both sites on PKA-I or PKA-II by site-selective analogue pairs e.g. 8-aminobutyloamino-cAMP plus 8-piperidino-cAMP or N6-benzoyl-cAMP plus 8-piperidino-cAMP respectively, significantly increased sensitivity of glomeruli to analogues. Our data suggest that activation of PKA-I or PKA-II might have an important role in the regulation of glomerular contractility.
Estimation of the glomerular filtration rate (GFR) and of the effective renal plasma flow (ERPF) by means of the test substances inulin and p-aminohippuric acid according to the steady state clearance measurement during the drop of the plasma level after the initially injection of an depot of the indicators was examined methodologically. The procedure should be repeatable in the same animal under conscious conditions. The results demonstrate that the described method is adequate with regard to accuracy, reproducibility and sensitivity for the estimation of the GFR, whereas limitations apply to calculation of the ERPF.
In sheep fed low-protein diets, renal PAH and inulin extractions are not affected by the fall in plasma urea level or in the renal plasma flow itself. The noted reduction in glomerular filtration rate is not due to a preglomerular shunt of arterial blood since the filtration fraction does not vary by comparison to sheep on regular diets. Thus, the reduction in renal plasma flow (PAH clearance), induced by low protein rations, is not dependent on any change in PAH extraction. This reduction is probably responsible for the simultaneous decrease of glomerular filtration.
Residualizing labels for protein, such as dilactitol-125I-tyramine (125I-DLT) and cellobiitol-125I-tyramine, have been used to identify the tissue and cellular sites of catabolism of long-lived plasma proteins, such as albumin, immunoglobulins, and lipoproteins. The radioactive degradation products formed from labeled proteins are relatively large, hydrophilic, resistant to lysosomal hydrolases, and accumulate in lysosomes in the cells involved in degradation of the carrier protein. However, the gradual loss of the catabolites from cells (t1/2 approximately 2 days) has limited the usefulness of residualizing labels in studies on longer lived proteins. We describe here a higher molecular weight (Mr approximately 5000), more efficient residualizing glycoconjugate label, inulin-125I-tyramine (125I-InTn). Attachment of 125I-InTn had no effect on the plasma half-life or tissue sites of catabolism of asialofetuin, fetuin, or rat serum albumin in the rat. The half-life for hepatic retention of degradation products from 125I-InTn-labeled asialofetuin was 5 days, compared to 2.3 days for 125I-DLT-labeled asialofetuin. The whole body half-lives for radioactivity from 125I-InTn-, 125I-DLT-, and 125I-labeled rat serum albumin were 7.5, 4.3, and 2.2 days, respectively. The tissue distribution of degradation products from 125I-InTn-labeled proteins agreed with results of previous studies using 125I-DLT, except that a greater fraction of total degradation products was recovered in tissues. Kinetic analyses indicated that the average half-life for retention of 125I-InTn degradation products in tissues is approximately 5 days and suggested that in vivo there are both slow and rapid routes for release of degradation products from cells. Overall, these experiments indicate that 125I-InTn should provide greater sensitivity and more accurate quantitative information on the sites of catabolism of long-lived circulating proteins in vivo.
A single-injection, double-isotope method for simultaneously determining glomerular filtration rate (GFR) and effective renal plasma flow (ERPF) in conscious, unrestrained rats was evaluated. 3H-inulin and 14C-tetraethylammonium bromide were used to determine GFR and ERPF, respectively. Using a modified, single exponential, 1-compartment, mathematical model, solute clearance was estimated, using a plasma radioactivity disappearance curve constructed from samples collected during a 60-minute period. In 12 healthy, conscious, adult male Sprague-Dawley rats, the mean (+/- SEM) GFR, ERPF, and filtration fraction were 5.65 +/- 0.40 ml/min/kg, 13.92 +/- 0.82 ml/min/kg, and 0.41 +/- 0.03, respectively. In 7 adult male Sprague-Dawley rats that had undergone a three-quarter nephrectomy 6 weeks prior to study, the mean GFR, ERPF, and filtration fraction were 2.69 +/- 0.36 ml/min/kg, 7.02 +/- 0.90 ml/min/kg, and 0.39 +/- 0.03, respectively. In 37 adult male rats in various stages of renal disease, the mean GFR and ERPF correlated significantly (r = 0.85, P less than 0.001 and r = 0.83, P less than 0.001, respectively) with the reciprocal of plasma creatinine. The single-injection, double-isotope technique yielded functional values similar to those reported for healthy rats in which other clearance methods were used. Using this technique, we were able to detect alterations associated with various degrees of renal functional loss. The technique enabled us to evaluate conscious, unrestrained rats, eliminated the need to collect urine, and required short blood collection times (60 min) and small volumes (0.1 ml) of plasma.
A double-isotope single-injection method without urine collection for the estimation of glomerular filtration rate (GFR) and effective renal plasma flow (ERPF) in dogs and cats was evaluated. The GFR was determined, using 14C-inulin and ERPF was determined, using [3H]tetraethylammonium bromide. Using a modified single exponential, 1-compartment mathematical model, the renal clearance of these solutes was estimated with a plasma radioactivity disappearance curve constructed from samples collected over a 150-minute time period. In 25 dogs, GFR, ERPF, and filtration fraction were 3.55 +/- 0.14 ml/kg/min, 10.51 +/- 0.72 ml/kg/min, and 0.34 +/- 0.02, respectively. In 25 cats, GFR, ERPF, and filtration fraction were 3.24 +/- 0.14 ml/kg/min, 8.14 +/- 0.53 ml/kg/min, and 0.39 +/- 0.02, respectively. This time-efficient and reliable method, using beta-emitting isotopes, yielded renal functional values well within the normal ranges reported by a variety of other isotopic and nonisotopic procedures. The advantages of the present procedure over previous double-isotope single-injection methods include the use of less costly, lower energy-using, and less penetrating beta emittors, as well as a shortened blood sampling schedule.
In 85 patients with ascertained chronic pyelonephritis the relations between the measured values of the combined PAH-inulin-clearance, the index of the adrenal cortex and other radiological findings were investigated. Here the determination of the cortex of the adrenal cortex resulted in a better correlation with the sizes clarification values than the calculation of the size of the kidney. By variance analysis (F-test) significant differences between the individual function groups became clear.
Copper cluster ions which contain 14 copper atoms and 12 penicillamine ligands produce no indications of toxicity when injected intravenously in doses of 12 mg/kg (as the hydrated sodium salt). These ions pass freely through the Bowman's capsules and are eliminated with the urinary effluent. The blood plasma and blood serum kinetics of the process may be followed with selectivity and sensitivity using copper's flame atomic absorbance at 324.7 nm, and a first order rate law with a half life of approximately ten minutes is observed. Clearance obtained by this method is inulin-like. The copper cluster ion does not readily permeate the erythrocyte membrane, and its distribution immediately following intravenous injection appears to be essentially that of the plasma volume. Since serum or plasma preparation for atomic absorbance measurements is minimal, the method might have applications in rapid determinations of renal clearance.
Immunoglobulin heavy chains have been shown to be encoded by at least 3 widely separated genetic elements, designated variable (V), diversity (D), and joining (J), which undergo rearrangement during somatic differentiation to produce the active gene form. The D segment codes for a portion of the 3rd hypervariable region and thus potentially contributes significantly to structural diversity in this portion of the molecule. Heavy chains from anti-inulin proteins are unusual in that they essentially lack a 3rd hypervariable region. Thus, if a D segment exists in these proteins, it is extremely short, possibly 1 to 2 amino acids, and more likely serves a framework function rather than introduces structural diversity in the 3rd hypervariable region. We have completed the heavy chain variable region amino acid sequence from proteins AMPC1 and T957 bringing to 6 the number of complete sequences from this group. All of these proteins lack a 3rd hypervariable region. In addition, substitutions are found within the J segments of AMPC1 and T957, which are unlikely to be generated by the recombination event. The occurrence of Pro at position 105 in both of these J segments in contrast to the Gln found in all other heavy chains using this J segment suggests the possible existence of a previously unidentified J segment gene.
The myeloma proteins binding inulin afford a unique opportunity to study the V region patterns of variation because of the similarity in the VL as well as the VH regions. The diversity patterns in both the VL and VH regions suggest these proteins are encoded by multiple, very similar V gene segments or that somatic mutation may repeatedly generate identical variants. Because of the close similarity in the V domains of these proteins and the extensive idiotypic analyses that have been carried out previously, several interesting conclusions can be drawn about the nature of idiotypic determinants. First, a single amino acid residue may be involved in determining multiple idiotypic determinants. Second, hapten-inhibitable idiotypes may depend on residues within and outside the hypervariable regions. Third, idiotypic similarity does not always predict a corresponding sequence similarity.