bluuebunny/crossref_metadata_2025 huggingface dataset:
Simulation of the metabolism and enterohepatic circulation of endogenous chenodeoxycholic acid in man using a physiological pharmacokinetic model
Authors: MOLINO G. , HOFMANN A. F. , CRAVETTO C. , BELFORTE G. , BONA B.
Published: March 2008

Abstract The metabolism and enterohepatic circulation of chenodeoxycholic acid (CDC), a major primary bile acid in man, has been stimulated using a multicompartmental physiological pharmacokinetic model which was previously reported and used to simulate the metabolism of cholic acid. The model features compartments and linear transfer coefficients. Compartments, which are defined as the pools of single chemical species in well defined anatomical volumes, are aggregated into nine ‘spaces’ based on anatomical and physiological considerations (liver, gall‐bladder, bile ducts, duodeno‐jejunum, ileum, colon, portal blood, sinusoidal blood, and general circulation). Each space contains several compartments which correspond to the compounds present in that space, for example, the compound in question and its biotransformation products. For CDC (as for cholic acid in the previous simulation) each space contains three compartments corresponding to the unconjugated bile acid, its glycine amidate, and its taurine amidate. Transfer coefficients, which denote the fractional amount of the compartment's contents exiting per unit time, are categorized according to function: flow, for example gall‐bladder contraction (which involves transfer of all substances contained in the space at the same fractional rate); biotransformation (which transfers the substrate from one compartment to another within the same space); or transport (which denotes movements between contiguous compartments, belonging to different spaces across a diffusion membrane or a cellular barrier). The model is made time‐dependent by incorporating meals which trigger gall‐bladder emptying and modify intestinal flow. The transfer coefficients in the cholic acid model were modified for the CDC model since (a) there is indirect evidence that CDC amidates (probably chenodeoxycholylglycine) are absorbed from the duodeno‐jejunum and (b) the first pass hepatic clearance of CDC species differs from that of cholyl species. The model was then used with all existing experimental data to simulate CDC metabolism in healthy humans over a 24‐h period during which three meals were ingested. Satisfactory agreement was obtained between simulated and experimental data indicating that this model continues to be useful for describing the metabolism of bile acids and may also be of value for describing the metabolism of drugs whose metabolism is similar to that of bile acids.
Pulmonary extraction of circulating noradrenaline in man
Authors: HENRIKSEN J. H. , CHRISTENSEN N. J. , RING‐LARSEN H.
Published: March 2008

Abstract Pulmonary plasma kinetics of endogenous noradrenaline (NA) and tritium labelled L‐noradrenaline (3H‐NA) was studied in fifteen subjects during pulmonary arterial catheterization. Plasma NA concentration in femoral artery ranged from 0·5 to 8·2 nmol l−1, mean 2·3 nmol l−1, which was not significantly different from that of age‐matched control subjects. The lungs extracted both endogenous NA and 3H‐NA significantly, but no significant pulmonary extraction of endogenous adrenaline was found. The pulmonary arterial‐systemic arterial extraction ratio of NA was mean 0·08 (n= 9) as compared to that of 3H‐NA: mean 0·07 (n= 8, NS). Likewise mean pulmonary clearances of NA and 3H‐NA were not significantly different (97 ml min−1x M−2v. 124 ml min−1x M−2, NS). Estimated whole‐body clearance of noradrenaline was mean 0·80 1 min−1x M−2(n= 6) while the pulmonary clearance amounted to 19% of this value. The small, but significant, pulmonary extraction of circulating noradrenaline implies that whole‐body clearance, as estimated from infusion rate and systemic arterial sampling, will be overestimated by approximately 7%. As pulmonary extraction of NA and 3H‐NA was almost identical, the results indicate no significant pulmonary contribution to circulating noradrenaline.
Gastrointestinal absorption of aluminium from single doses of aluminium containing antacids in man
Authors: & R. WEBERG , BERSTAD A.
Published: March 2008

Abstract Ten subjects with normal renal function were given different single doses of aluminium containing antacids (1, 4, or 8 tablets). The antacid tablets (aluminium content 244 mg tablet‐1) were chewed and swallowed either with water, with orange juice, or with citric acid solution. There was a marked increase in serum concentration of aluminium when the antacids was ingested with citric acid (P<0·001) or with orange juice (P<0·05). When antacids were taken with water, a slight, but significant increase in serum aluminium concentration was seen with 4, but not with 1 or with 8 tablets. Following all doses of antacid, a significant increase in 24 h urinary excretion of aluminium was seen. The estimated absorption of aluminium was 8 and 50 times higher when antacids were taken with orange juice or with citric acid, respectively, than when taken with water. Thus, measurable quantities of aluminium are absorbed from single oral doses of antacids. The absorption is substantially enhanced by concomitant ingestion of citric acid.
Haemodynamic and hormonal responses to exercise: Studies in patients with diabetes mellitus and adrenomedullary deficiency
Authors: BARNETT A. , MASLOWSKI A. , LIVESEY J. , NICHOLLS G. , IKRAM H. , ESPINER E.
Published: March 2008

Abstract. The haemodynamic and hormonal responses of patients with autonomic neuropathy and others with adrenomedullary deficiency were compared with mild hypertensives (range of blood pressure 90–100 mmHg diastolic and 140–160 mmHg systolic) and uncomplicated diabetics during standard exercise and postural manoeuvres using continuous arterial blood pressure monitoring. There was no difference in these parameters between the groups when at rest or on standing. During exercise there was no significant difference in blood pressure and heart rate between the groups and all showed significant increases in plasma noradrenaline (mean rise for all groups 2730–22105 pm l‐1, P<0·03) and (in all but the adrenalectomized subjects) adrenaline (mean rise for remaining three groups 946–3384 pm l‐1, P<0·03; adrenalectomized group showed no rise). The group with autonomic neuropathy showed a significant rise in plasma cortisol from basal 450 ± 40 to 845 ± 72 nm l‐1, P < 0·005 after exercise, but the other groups showed no significant change. The maximum level attained for plasma cortisol in the adrenalectomized subjects after exercise was significantly less (260 ± 41 nm l‐1) than in the diabetic groups (696 ± 68 nm l‐1 (non‐neuropaths), 845 ± 72 nm l‐1 (neuropaths), P<0·01).

We have demonstrated normal blood pressure and pulse responses to posture and sustained exercise in diabetics with autonomic neutropathy. The findings of similarly normal responses in patients with adrenomedullary deficiency suggest that circulating adrenaline is not obligatory to a normal haemodynamic response to exercise.
Warfarin binding to plasma albumin, measured in patients and related to fatty acid concentrations
Authors: LARSEN F. GRØNHØJ , LARSEN C. GRØNHØJ , ANDERSEN S. , NØRGAARD A. , HANSEN H. E. , BRODERSEN R.
Published: March 2008

Abstract. A method for determination of reserve albumin equivalent for binding of warfarin as previously described [1] has been used for assessing the influence of non‐esterified fatty acid concentration (NEFA) on binding of warfarin to human serum albumin (HSA). Reserve albumin concentration can be used for calculation of the expected fraction of bound warfarin in serum. It is shown in vitro that binding of warfarin increases with added oleate up to 4 mol of oleate per mol of albumin and then decreases. Twenty‐four patients on permanent warfarin treatment showed no correlation of serum albumin and reserve albumin concentrations (r=0·10, P>0·50) indicating that warfarin binding is governed by other factors. However, in the same patients there was a significant correlation between reserve albumin concentration and NEFA/HSA (r= 0·54, P < 0·01). In one human volunteer changes of NEFA were provoked by strenuous work and it was found that reserve albumin concentration increased with NEFA concentration as expected from the in vitro findings (r= 0·90, P< 0·001). Five uraemic patients on permanent warfarin treatment showed increasing reserve albumin concentration with increasing NEFA concentration induced by heparin. These findings indicate that, both in vitro and in vivo, the reserve albumin concentration for binding of warfarin and hence the free warfarin concentration is markedly influenced by NEFA concentration. This may add to the understanding of warfarin dose requirement during anticoagulant therapy.
Survival of gentamicin‐loaded carrier erythrocytes in healthy human volunteers
Authors: EICHLER H. G. , RAMEIS H. , BAUER K. , KORN A. , BACHER S. , GASIĆ S.
Published: March 2008

Abstract. Resealed erythrocytes are potential slow release carriers for drugs and enzymes. We have investigated carrier erythrocyte survival in human volunteers using gentamicin (G) as encapsulated cell marker; G was readily incorporated into red cells by hypo‐osmotic dialysis (87% efficiency of incorporation) and did not exit from carrier cells in vitro. Six healthy young volunteers were injected with 59 ± 7 ml carrier erythrocytes containing 56 ± 13 mg G. G levels were measured in plasma and haemolysed whole blood by RIA. After an initial phase of cell loss (up to 4·5 h post‐injection) the carrier erythrocytes survived in circulation with a half‐life of 22 days, as was indicated by intracellular G concentration. G levels were detectable in plasma during the first 90 min after injection. This indicates haemolysis of some carrier cells. In conclusion, carrier erythrocytes appear to circulate longer than any other drug carrier under investigation and may well serve as innocuous slow release system.
Ex vivo perfusion of plasma over protein A columns in human mammary adenocarcinoma. Role of the Fc‐binding capacity of protein A in the side effects and the tumoricidal response
Authors: KINET J. P. , BENSINGER W. I. , BALLAND N. , SAINT‐REMY M. , FRANKENNE F. , HENNEN G. , MAHIEU Ph.
Published: March 2008

Abstract. Plasma of twelve patients presenting with a metastic mammary adenocarcinoma was perfused ex vivo over columns of protein A covalently linked to crystalline silica. The plasma of seven patients (group A) was perfused over columns of protein A exhibiting a normal Fc‐binding capacity and the plasma of five (group B) over columns of protein A in which the Fc‐binding capacity was destroyed. In group A, all patients experienced acute, easily manageable, side effects (hypotension, chills, mild fever, leucocytosis and pain in tumour sites) during or immediately after the immunoadsorption procedures, and three exhibited an objective partial regression after two to five sessions. In contrast, none of the patients from group B developed any acute side effects and all showed evident progression of their disease during the treatment. Tumour cells in all stages of destruction, sometimes surrounded by extensive fibrosis, were seen in biopsies of patients A. However, focal areas of active tumour proliferation were always present in these patients. These data confirm that ex vivo perfusion over protein A columns of plasma from patients with cancer can induce a tumoricidal response in some instances and show that the Fc‐binding capacity of protein A is most probably responsible for the necrolytic response and the side effects.
Change in very low‐, low‐, and high‐density lipoproteins during lipid lowering (bezafibrate) therapy: studies in type IIA and type IIb hyperlipoproteinaemia
Authors: GAVISH DOV , OSCHRY YITZCHAK , FAINARU MENAHEN , EISENBERG SHLOMO
Published: March 2008

Abstract. The effects of lipid lowering therapy (bezafibrate) on plasma lipoproteins was investigated in twelve patients with familial hypercholesterolaemia (type IIA) and eight with familial combined hyperlipidaemia (type IIB). Bezafibrate caused a decrease of plasma cholesterol, plasma triglycerides, plasma apolipoprotein B, VLDL cholesterol and LDL cholesterol and an increase of HDL cholesterol. Post‐heparin plasma lipoprotein and hepatic lipase activities increased in both groups (significant only in type IIB). Lipoprotein composition showed the following changes: Increased protein and phospholipids and decreased triglycerides and cholesteryl esters in VLDL. Decreased protein and triglycerides and increased free and esterified cholesterol in LDL. Decreased triglycerides and increased phospholipids in HDL. Cholesteryl ester to protein ratios decreased in VLDL and increased in LDL. The hydrated density of LDL (both groups) and of HDL3 (type IIB) decreased following bezafibrate therapy. These changes were in general similar to those observed in hypertriglyceridaemic patients and could be ascribed, at least in part, to the increase of plasma lipase activities and the decrease of lipid transfer reactions. Comparing the present data with that previously reported, it was found that bezafibrate caused decreased LDL cholesterol in types IIA and IIB but increased levels in type IV. This change was correlated with the initial plasma triglycerides (r= 0·74, P < 0·0001) and initial plasma LDL cholesterol (r= 0·66, P < 0·001). It is concluded that varied response of LDL to therapy reflects a complex interaction of metabolic events, including changing rates of VLDL conversion to LDL, lipoprotein compositional changes and effects of therapy on LDL degradation rates.
Increase in type I and type IV collagenolytic activity in primary cultures of keratoconus cornea
Authors: IHALAINEN A. , SALO T. , FORSIUS H. , PELTONEN L.
Published: March 2008

Abstract. The collagenolytic activities were assayed in fibroblast cultures established from ten keratoconus and six control corneal explants. The assays included those for both type I and type IV collagenase. The amount of free, directly assayable type I collagenase was highly increased in the media of keratoconus primary cell cultures. Also the activity of type IV collagenase was increased significantly in these cultures but was detectable only after proteolytic activation. The total hydroxyproline content of keratoconus corneas was decreased when compared to controls. However the activity of the prolyl‐4‐hydroxylase, reflecting the biosynthesis of collagen, was higher in the keratoconus corneal tissue, either expressed per DNA, soluble protein or hydroxyproline content of corneas. The enhancement in collagenolytic processes could explain the pathological tissue destruction in keratoconus corneas and this enhancement is maintained still in primary cultures of keratoconus corneal fibroblasts.
Demonstration of neutrophil chemotactic activity in the sputum of cystic fibrosis patients with Pseudomonas aeruginosa infection
Authors: KHARAZMI A. , SCHIØTZ P. O. , HØIBY N. , BAEK L. , DÖRING G.
Published: March 2008

Abstract. The pathogenesis of tissue damage in the lungs of cystic fibrosis patients with chronic P. aeruginosa infection is quite complex and not well understood. Inflammatory cells, particularly neutrophils, are accumulated in the damaged tissues and in the sputum. This study demonstrates the presence of a heat‐stable neutrophil chemotactic factor(s) in the sputum of CF patients. The chemotactic activity seems to be associated with the endotoxin present in the sputum. Chemotaxis of sol phase sputum was determined in a modified Boyden chamber assay. It was found that the sputum obtained from the patients showed strong chemotactic activity for peripheral blood neutrophils of normal individuals. The activity was greater than twice that of casein, a strong neutrophil chemo‐attractant. Sputum at about dilution of 1:50 exhibited chemotactic activity equal to that of casein. Heat treatment of the sputum at 56°C for 30 min, to inactivate complement, and at 100°C for 15 min, to denature other proteins, somewhat reduced the chemotactic activity, but there was still strong chemotactic activity. The presence of endotoxin was demonstrated in both the non‐heated and the heated samples by LAL and rocket immunoelectrophoresis. It is concluded that the sputum of CF patients contain chemotactic activity of heat‐stable nature and most likely of bacterial origin endotoxin. These factors are involved in attraction of neutrophils to the lungs and sputum of these patients and contribute to the tissue damage of cystic fibrosis.
Bile acids and plasma high density lipoproteins: biliary lipid metabolism in fish eye disease
Authors: ANGELIN BO , CARLSON LARS A.
Published: March 2008

Abstract. Cholesterol in plasma high density lipoproteins (HDL) has been proposed to serve as preferential precursor for bile acid biosynthesis in the liver. Furthermore, a negative relationship between plasma levels of HDL cholesterol and biliary saturation with cholesterol has been reported in healthy females. We have performed metabolic studies on a female patient with fish eye disease, a familial condition where plasma HDL levels are reduced by 90% and the concentration of plasma triglycerides is moderately increased. Both the total production of bile acids and the net steroid ‘balance’ (reflecting total body cholesterol synthesis) were within the range seen in normolipidaemic as well as in hypertriglyceridaemic females. Also the biliary lipid composition and cholesterol saturation of bile were normal. A qualitative abnormality in the bile acid pattern was observed, however, in that the ratio between the synthesis of cholic acid and chenodeoxy‐cholic acid was reduced. It is concluded that a low HDL cholesterol level is not necessarily associated with quantitative abnormalities of biliary lipid metabolism. The abnormal bile acid synthesis ratio may reflect changes in the hepatic precursor pools of cholesterol as the consequence of HDL deficiency, however.
Glucoregulation in acute liver failure
Authors: VILSTRUP H. , IVERSEN J. , TYGSTRUP N.
Published: March 2008

Abstract. Five patients with fatal acute liver failure, given 5 g h‐1 of glucose for the previous 12 h, were investigated by the hyper‐ and euglycaemic glucose ‘clamp’ technique, and the results compared with reported control values. Initial average blood glucose concentration was normal (6·0 mmol l‐1, range 5·0–8·8). Plasma insulin and C‐peptide concentrations were increased about tenfold (1450 pmol l‐1, range 330–4021, and 3000 pmol l‐1, range 670–7650, respectively). The whole body glucose metabolic rate was decreased to about half control values (21 μmol min‐1 kg‐1, range 6–28) and the insulin sensitivity of the glucose metabolism was decreased to about 15% (9·4 m3 min‐1 kg‐1, range 3·6–14·4). The calculated metabolic clearance of insulin was normal (520 ml min‐1 (m2)‐1, range 305–1027) and the calculated systemic delivery rate of insulin was about sixfold increased (1135 pmol min‐1 (m2)‐1, range 474–2010). The initial glucagon concentrations were fifty‐fold increased (550 pmol l, range 72–1309) and not suppressible by glucose and insulin. The patients thus exhibited pronounced insulin insensitivity and hyperinsulinaemia, attributable primarily to pancreatic hypersecretion. The reason for the relation between, and the pathogenetic importance of, these findings is not known.
Representativity of regional to total bone mineral in healthy subjects and ‘anticonvulsive treated’ epileptic patients. Measurements by single and dual photon absorptiometry*
Authors: GOTFREDSEN A. , BORG J. , NILAS L. , TJELLESEN L. , CHRISTIANSEN C.
Published: March 2008

Abstract. Dual photon (153Gd) and single photon (125I) absorptiometry were used to measure the regional bone mineral content (BMC) and density (BMD), as well as the total body bone mineral content (TBBM) and density (TBBD), in sixty‐nine healthy subjects and in twenty‐three epileptics on phenobarbitone. The BMCs (and BMDs) of all regions were significantly correlated to each other and to the TBBM (and TBBD). No difference in the ability to discriminate between the different study groups was found for the various regions, excepting the BMD of the head. The relationship between the forarm BMC and TBBM was highly significant, and indentical in the five groups. The relationships between spinal BMC and forearm BMC, and TBBM differed in the five groups. It is concluded that some local measurement may be used as estimates of the total body bone mineral in some groups of patients with minor metablic bone disease and healthy subjects.
Intestinal permeability and lactose hydrolysis in human rotaviral gastroenteritis assessed simultaneously by non‐invasive differential sugar permeation
Authors: NOONE C. , MENZIES I. S. , BANATVALA J. E. , SCOPES J. W.
Published: March 2008

Abstract. Changes in intestinal permeability and lactose hydrolysis have been investigated in three adults and fifteen infants with acute rotaviral gastroenteritis by differential sugar absorption. The method involves chromatographic measurement of urinary lactose, lactulose and L‐rhamnose excretion following combined ingestion in an iso‐osmolar test solution. All patients had abnormal intestinal permeability indicated by raised urine lactulose/L‐rhamnose excretion, ratio of percentages recovered in 5 h, of 0·462 (0·100–1·227) mean and range, compared with 0·027 (0·008–0·052) for healthy controls (P < 0·001). Ten patients also had urinary lactose/lactulose excretion ratios raised above the normal range (0·014–0·41, mean 0·258) during their acute illness, indicating impaired intestinal lactose hydrolysis. Both indices had become normal 4 weeks after the acute illness, serial investigation of five patients showing that improvement was complete much earlier. Except for the short duration these changes are similar to those associated with villous atrophy in coeliac disease. The test procedure was verified with respect to intestinal lactose hydrolysis by demonstrating a linear relationship between lactose/lactulose excretion and log jejunal mucosal lactase activity by in vitro assay (R2= 0·95) in a further group of subjects. Differential lactose/lactulose/L‐rhamnose absorption provides a non‐invasive and sensitive index of small intestinal integrity of value for the interpretation of prolonged or otherwise complicated enteritis and the distinction of primary secondary intestinal lactase deficiency.
Effects of indomethacin, prostaglandins E2 and I2 on the tone of human isolated femoral arteries
Authors: HADHÁZY P. , NAGY L. , DÖMÖTÖR L. , MAGYAR K.
Published: March 2008

Abstract. Strips of endothelium‐denuded femoral arteries from operated patients were set up for isometric recording. Indomethacin (IND, 3 μmol l‐1) enhanced basal tension of the arteries from 0·13 ± 0·04 to 0·86 ± 0·12 mN (P < 0·001; n= 16) and potentiated the contractile responses of the strips to noradrenaline (NA); EC50 for NA was 1·5 ± 0·3 μmol l‐1 (n= 6) in the absence, and 0·4 ± 0·07 μmol l‐1 (n= 6) in the presence of IND (P < 0·01). PGI2 produced dose‐related relaxation in IND‐treated vessels, its IC50 being 15·0 ± 1·3 nmol l‐1. Low concentrations of PGE2 (0·85–8·5 nmol l‐1) reduced whereas its higher concentrations (28–85 nmol l‐1) increased smooth muscle tone in the presence of IND. These results indicate that human femoral arteries—unlike femoral arteries of some laboratory animals—are highly sensitive to cyclooxygenase inhibition as well as to PGI2 and PGE2.
Serotonin increases the velocity of propagation and frequency of the migrating myoelectric complexes
Authors: COELHO J. C. U. , GOUMA D. J. , MOODY F. G. , LI Y. F. , WEISBRODT N. W.
Published: March 2008

Abstract. The effect of serotonin on the myoelectric activity of the gastrointestinal tract was evaluated in seven opossums. Continuous intravenous administration of serotonin reduced the cycle duration of the migrating myoelectric complex and increased the velocity of propagation of the phase III. These changes were dose‐dependent and were observed only with high doses of serotonin of 0·1 mg kg‐1 h‐1 or more. Infusion of 0·01 mg kd‐1 h‐1 had no effect on the motility of the gastrointestinal tract. The motility changes occurred in all segments of the gastrointestinal tract studied and were characterized by a continuous and organized increase in the velocity of propagation of the activity front (phase III) of the migrating myoelectric complex from the antrum to the terminal ileum. The cycle duration of the two migrating myoelectric complexes following administration of methysergide at 1·0 mg kg‐1 was similar to the control migrating myoelectric complexes. We concluded that continuous infusion of serotonin in the opossum increases the velocity of propagation of the phase III of the migrating myoelectric complex from the antrum to the terminal ileum.
Protoporphyrinogen oxidase and porphobilinogen deaminase in variegate porphyria
Authors: MEISSNER P. N. , DAY R. S. , MOORE M. R. , DISLER P. B. , HARLEY E.
Published: March 2008

Abstract. Two enzymes of the haem biosynthetic pathway were investigated in patients with variegate porphyria. Protoporphyrinogen oxidase in cultures of Epstein‐Barr virus transformed lymphoblasts from twenty‐seven patients showed a mean maximal velocity (Vmax) of 0·39 ± 0·08+ nmol of protoporphyrin mg protein‐1 h‐1, a 52% reduction (P < 0·001) from a non‐porphyric control group (0·82 ± 0·10). Km values (1·00 ± 0·27 μM) did not differ significantly (P > 0·05) from control values in any of the patients. The mean Vmax of porphobilinogen deaminase in the cultures was 1·50 ± 0·18 nmol of uroporphyrin mg protein‐1 min‐1, a 24% reduction (P < 0·001) from controls (1·94 ± 0·14). Mean porphobilinogen deaminase activity in the erythrocytes of twenty‐one patients with variegate porphyria was 8·37 ± 1·99 nmol of uroporphyrin 1 erythrocytes‐1 s‐1, a 28% reduction (P < 0·001) from normal (11·98 ± 2·11). The reduced activities of these two enzymes comply with the expression of variegate porphyria during its quiescent and acute phases.
Calcium absorption following small bowel resection in man. Evidence for an adaptive response
Authors: COLETTE C. , GOUTTEBEL M. C. , MONNIER L. H. , SAINT‐AUBERT B. , JOYEUX H.
Published: March 2008

Abstract. Seventeen patients who had undergone extensive small bowel resection were studied for calcium absorption (FACa) and plasma vitamin D metabolites. FACa was measured by a double radiotracer technique and expressed as percentage of total oral dose. FACa was decreased compared with controls (34%, range: 3–46 v 65%, range: 57–73, P < 0·01). A positive correlation (r= 0·49, P= 0·05) was found between FACa and the remaining length of small bowel (SBL). As wide variations in both SBL and duration after surgery were observed among the seventeen investigated patients, we were led to individualize less heterogeneous subgroups of patients. Better correlations were found when the patients were divided into two subgroups according to whether the time interval between the resection and the investigation was shorter (r= 0·75, n= 11, P < 0·02) or longer (r= 0·89, n= 6, P= 0·05) than 2 years. In thirteen patients who had a SBL shorter than 100 cm, a positive correlation was observed between FACa and the time interval after surgery (months): r= 0·65, P < 0·05. Plasma 1,25 (OH)2D was markedly reduced in the whole group (31 pmol l‐1, range: 8–108) compared with controls (103 pmol‐1, range: 59–134, P < 0·01). The present study shows that in extensively small bowel resected patients, calcium absorption is reduced, the alteration being dependent both on the length of the remnant small bowel and on the time after surgery. These results confirm that adaptive changes occur with time, but it is difficult to conclude whether a specific segment of the intestine is involved in the adaptative response.
Primary hyperparathyroidism: evaluated by 47Calcium kinetics, calcium balance and serum bone‐Gla‐protein
Authors: CHARLES P. , MOSEKILDE L. , JENSEN F. TAAGEHØJ
Published: March 2008

Abstract. Combined 47Calcium kinetic and calcium balance studies with correction for dermal calcium loss were performed in thirteen patients with primary hyperparathyroidism (PHP), in whom serum bone‐Gla‐protein (S‐BGP) was measured, and in ten matched controls. Dietary calcium was normal in PHP but both net (7·9±1·4 mmol Ca day‐1 in PHP v. 3·5±0·9 mmol Ca day‐1 in normals (mean±SE)) and true (11·1±1·6 v. 6·8±0·9 mmol Ca day‐1) intestinal absorbed calcium were enhanced (P < 0·05). The renal calcium excretion (10·9±0·8 v. 5·1±0·4 mmol Ca day‐1, P < 0·001) and the dermal calcium loss (2·5±0·3 v. 1·5±0·1 mmol Ca day‐1, P < 0·02) were increased in PHP. Both patients and controls were in a negative calcium balance (P < 0·01 and P < 0·001, respectively) without any difference between the groups (P > 0·10). Mineralization (12·0±1·7 v. 4·8±0·8 mmol Ca day‐1, P < 0·02) and resorption rates (17·6±2·5 v. 7·9±0·6 mmol Ca day‐1, P < 0·02) were increased in PHP and S‐BGP correlated positively to both variables (r= 0·64, P < 0·05 and r= 0·62, P < 0·05, respectively). Serum immunoreactive parathyroid hormone correlated positively to serum calcium (r= 0·69, P < 0·01) but not to the calcium kinetic data.
Increased α2‐ but similar β‐adrenergic receptor activities in subcutaneous gluteal adipocytes from females compared with males
Authors: RICHELSEN B.
Published: March 2008

Abstract. α
2 and β‐adrenergic binding and action were studied in subcutaneous adipocytes from the gluteal region in females and males. The β‐selective antagonist [3H]dihydroalprenolol and the α2‐selective antagonist [3H]yohimbine were used to identify the β‐ and the α2‐receptor, respectively. The biological effects mediated by these receptors were determined by measuring the glycerol release induced by isoproterenol (β‐receptor agonist) and by clonidine (α2‐receptor agonist). The study consisted of health volunteers (eighteen females and fifteen males). Compared to men the α2‐receptor binding was increased by 73% (P < 0·01) in adipocytes from females. From Scatchard analysis it was determined that the increased binding was due to an increased receptor number (438 v. 262 fmol mg‐1 protein, P < 0·001) with unaltered Kd (1·18 v. 1·35 nmol l‐1, P > 0·05). This increased α2‐receptor binding in female and adipocytes was associated with a significantly increased sensitivity (P < 0·05) and maximal antilipolytic effect of clonidine (P < 0·05). The β‐receptor binding was similar in adipocytes from females and males. However, isoproterenol was significantly more lipolytic in female adipocytes (P < 0·01). Since the combination of theophylline and adenosine deaminase also was significantly more lipolytic in female adipocytes the enhanced effect of isoproterenol then seemed to be due to mechanisms not directly related to the hormone‐β‐receptor binding. Finally, the mixed β‐ and α2‐receptor agonist, adrenaline showed biphasic effects on lipolysis, with stimulatory effect at low concentrations (< 500 nmol l‐1) and pronounced inhibitory effect at higher concentrations (> 1 μmol l‐1). However, at low concentrations of adrenaline the lipolytic effect was significantly reduced in female gluteal adipocytes (P < 0·05), whereas the inhibitory effect was similar between females and males. It is concluded that female gluteal adipocytes possessed more α2‐adrenergic receptors than male adipocytes. This increased binding was accompanied by enhanced antilipolytic effect of clonidine and reduced lipolytic effect of low concentrations of adrenaline. Thus, it is suggested that the increased α2‐receptors in female gluteal adipocytes might be related to the enhanced tendency for females to accumlate fat in this region.
Effects of thyroid hormone and β‐adrenoceptor blocking agents on urinary excretion of 3‐methylhistidine and plasma amino acids in man
Authors: ADLERBERTH A. , JAGENBURG R. , LINDSTEDT G. , STENSTRÖM G. , HASSELGREN P.‐O.
Published: March 2008

Abstract. The aim of this investigation was to study the effect of β‐adrenoceptor blockade on alterations in protein metabolism induced by administration of 3,5,3′‐triiodothyronine (T3) to man. Urinary excretion of 3‐methylhistidine and plasma concentrations of amino acids were measured in seven healthy subjects following 1 week's administration of T3 alone or T3 in combination with the selective β1‐adrenoceptor blocking agent metoprolol or the non‐selective β‐adrenoceptor blocking agent propranolol. Urinary excretion of 3‐methylhistidine and plasma concentrations of valine, methionine, lysine, tyrosine, phenylalanine, isoleucine, leucine, and total essential and branched chain amino acids increased following administration of T3, probably in part reflecting accelerated muscle proteolysis. Neither metoprolol nor propranolol normalized 3‐methylhistidine excretion or plasma concentrations of amino acids during T3 treatment. The results indicate that metabolic alterations induced by T3 and giving rise to enhanced 3‐methylhistidine excretion and elevated concentrations of plasma amino acids are not normalized by β‐adrenoceptor blockade.
Differing attitudes of industry and academia towards controlled clinical trials
Authors: BLUM A. L. , CHALMERS T. C. , DEUTSCH E. , KOCH‐WESER J. , LANGMAN M. , ROSEN A. , TYGSTRUP N. , ZENTGRAF R.
Published: March 2008

Abstract. A consensus conference was held in 1984 on controversial issues concerning controlled clinical trials. Thirty‐six individuals working in academic institutions, forty‐six in industry and twelve in regulatory authorities participated. Academics accepted and industrial representatives rejected the following:

existing regulations cannot cope with the rate at which new treatments develop;

drug companies may be reluctant to undertake surveillance programmes because sales will fall if adverse reactions are detected;

novel remedies should not be promoted before extensive post‐marketing surveillance;

third parties should finance trials promising to reduce the costs of illness and

trialists should be separated from sponsors in data analysis and interpretation, the investigator owning the data unless stated otherwise.

Industrial representatives supported and academics rejected the following:

government price control inhibits drug development and

a multicentre trial can be justified simply by the wish to speed drug registration.
Calcium‐binding protein from human small intestine. Purification and characterization of a 10 000 molecular weight protein
Authors: STAUN M. , SJÖSTRÖM H. , NORÉN O.
Published: March 2008

Abstract. A calcium‐binding protein (CaBP) was purified from human small intestinal mucosa by ammonium sulphate fractionation, gel filtration and chromatofocusing. Antibodies against CaBP were raised in rabbits and CaBP was then isolated from human intestinal cytosol by a one‐step immunoadsorbent procedure. In polyacrylamide gel electrophoresis in the presence of sodium dodecyl sulphate CaBP migrated as a single band corresponding to a molecular weight of 10 000. The calcium‐binding ability of CaBP was demonstrated by increased electrophoretic mobility of CaBP in the presence of EDTA as demonstrated by immunoblotting of agarose gels. CaBP antibody showed no cross reaction with cytosolic proteins of duodenum from rat or pig. The present study suggests that molecular properties and distribution of human intestinal CaBP is comparable to those of intestinal CaBP detected in lower mammalian species.
Effects of intra‐arterial prostaglandin E1 in patients with peripheral arterial occlusive disease
Authors: CREUTZIG A. , CREUTZIG H. , ALEXANDER K.
Published: March 2008

Abstract. The effects of intraarterially administered prostaglandin E1 (PGE1) on macrocirculatory, microcirculatory and metabolic parameters in patients with peripheral arterial occlusive disease were studied. Nutritive calf muscle blood flow, as determined with the xenon‐clearance technique, and muscle tissue oxygen pressure increased markedly in patients with obliterations of the femoral artery. Transcutaneous PO2 as indicator for cutaneous blood flow increased in prestenotic regions dose‐dependently whereas there was a clear poststenotic decrease during the infusion period. High lactate/pyruvate ratios in the femoral vein were significantly decreased by PGE1 treatment. PO2 in the femoral vein increased significantly. Thus, PGE1 has some beneficial effects on muscle circulation in these patients.
Evaluation of low dose anaphylatoxic peptides in the pathogenesis of the adult respiratory distress syndrome (ARDS). Monitoring of early C5a effects in a guinea‐pig in vivo model after i.v. application**
Authors: HOFFMANN T. , BÖTTGER E. C. , BAUM H. P. , DENNEBAUM R. , HADDING U. , BITTER‐SUERMANN D.
Published: March 2008

Abstract. A guinea‐pig in vivo model is presented that allows the infusion of purified C5a via a central vein catheter and the monitoring of its effects on granulocytes and platelets, the most important cells in the pathogenesis of several lung disorders, e.g. shock lung. After the infusion of C5a, which was adjusted to a quantity that caused slight and transient alterations of lung physiology, granulocytes disappeared from circulation within 1 min. Simultaneously the granulocyte content of the lung increased about three‐fold as judged by histological evaluations. Morphologic destructions were not observed. After the drop a rebound of circulating Polymorpho‐nuclear leucocytes (PMN) occurred, which was significantly higher than control values and the appearance of banded cells indicated a mobilization from bone marrow stores. Studies with 51‐chromium labelled PMNs revealed that most, but not all, of the granulocytes returned to circulation after transient sequestration. The number of platelets also decreased after C5a infusion, but the rebound was delayed compared with the PMNs and did not exceed control values. The changes in circulating cells, lung histology, and lung physiology are comparable to those occurring during the onset of shock lung and thus strengthen the supposed importance of C5a concerning the pathogenesis of that syndrome.
Pancreatic secretion in the rat influenced by the low molecular weight serine proteinase inhibitor Gabexate mesilate
Authors: KEIM V. , GÖKE B.
Published: March 2008

Abstract. The effect of intravenous or intragastric administration of the synthetic proteinase inhibitor Gabexate mesilate (GM) on the pancreas of rats was investigated. Infused intravenously at 4 mg kg‐1 h‐1, GM inhibited both basal or cerulein (0·2 μg kg‐1 h‐1)‐stimulated pancreatic protein secretion. Intracellular transport and secretion of newly synthesized pancreatic enzymes was not influenced by intravenous infusion of GM. Intragastric administration of GM (400 mg kg‐1) on four consecutive days increased pancreatic wet weight, protein and enzyme content of the gland. A preferential increase of proteinases above glucosidases was observed. Pancreatic lobules from inhibitor‐treated rats released 30% less amylase in response to cerulein or carbachol when the rate of discharge was expressed in percent of initial content. Expressed in ku amylase/μg DNA secretion rate was two‐fold higher than in controls. In pancreatic duct cannulated rats GM (400 mg kg‐1 h‐1), introduced intragastrically on five consecutive days, stimulated volume‐bicarbonate and protein secretion rate, the secretory response on the fifth day being significantly higher than on the first day. Enzyme pattern in pancreatic juice changed characteristically: mainly the amount of acidic proteinases increased, whereas the amount of the basic isoforms was altered only slightly.
Role of polyamines in intestinal adaptation in the rat
Authors: HOSOMI M. , STACE N. H. , LIRUSSI F. , SMITH S. M. , MURPHY G. M. , DOWLING R. H.
Published: March 2008

Abstract. The cellular mechanisms controlling adaptive intestinal mucosal hypo‐ and hyperplasia are poorly understood but changes in tissue polyamine levels and in the activity of the key enzymes controlling their synthesis (ornithine decarboxylase: ODC) and degradation (diamine oxidase: DAO) have been implicated. Therefore, in two models of adaptive mucosal hyperplasia (pancreatico‐biliary diversion, PBD, achieved by surgically transposing the jejunum to lie between pylorus and ampulla of Vater, and 90% small bowel resection, SBR‐both studied 8 weeks after surgery) and in one model of hypoplasia (8 days total parenteral nutrition) we measured indices of mucosal mass (wet weight, protein and DNA per 10‐cm intestine), the growth‐associated polyamines (putrescine, spermidine and spermine per 10‐cm intestine and per mg DNA) and DAO activity in the duodenum, five 10‐cm segments of jejunum, five 10‐cm segments of ileum and in the colon, and compared the results with those found in transected or unoperated controls. The results for the indices of mucosal mass confirmed that TPN led to a modest degree of small bowel mucosal hypoplasia whilst PBD, and particularly 90% SBR, stimulated marked adaptive hyperplasia. There were corresponding changes in the amounts of putrescine and spermidine (but not of spermine)—not only when the results were expressed per unit length but also when calculated per mg mucosal DNA and in the ratio of spermidine:spermine. There was an increasing proximal‐to‐distal gradient in mucosal DAO per unit length intestine in all experimental groups but when the results were expressed per mg DNA, the ileal DAO levels were significantly reduced in the PBD and resection groups, when compared with the controls. These data support the hypothesis that polyamines play a major, and perhaps a controlling, role in regulating adaptive intestinal mucosal growth.
Cholesterol absorption efficiency regulates plasma cholesterol level in the Finnish population
Authors: KESÄNIEMI Y. A. , MIETTINEN T. A.
Published: March 2008

Abstract. Efficiency of cholesterol absorption in the variation of plasma cholesterol level was studied in a random sample of middle‐aged Finnish men. Compared with the subjects in the highest decile of plasma cholesterol, those in the lowest decile had a lower cholesterol absorption and, as measured with the serum contents of the cholesterol precursor sterols lanosterol and lathosterol, a higher cholesterol synthesis, the values for the subjects in the middle decile falling inbetween. Also, the serum content of betasitosterol, a plant sterol used as an additional indicator of cholesterol absorption, was high in the highest decile and low in the lowest decile of the plasma low density lipoprotein (LDL) cholesterol level. Among the whole study group the fractional absorption of cholesterol was positively correlated with the plasma cholesterol level, and a negative correlation was observed between the amount of absorbed dietary cholesterol and the cholesterol synthesis. Thus, the efficiency of cholesterol absorption has an important role in the determination of the plasma cholesterol level among the Finnish male population.
Changes in serum lipoproteins in humans following the infusion of a fat emulsion containing medium‐ and long‐chain triglycerides
Authors: HAILER S. , WOLFRAM G. , ZÖLLNER N.
Published: March 2008

Abstract. A fat emulsion containing equal parts of medium‐chain triglycerides (MCT) and long‐chain triglycerides (LCT) and emulsified with egg phospholipids (Lipofundin MCT 10%®) was compared with LCT emulsions (Intralipid 10%®, egg phospholipids; Lipofundin S 10%®, soya phospholipids) in six volunteers, using 4‐h periods of infusion and doses of 0·15 g kg‐1 body h‐1. At the end of infusion very low density lipoprotein (VLDL) triglyceride concentrations were highest with Intralipid, marginally less with Lipofundin MCT and lowest with Lipofundin S. With Lipofundin MCT infusion the proportions of free mediumchain fatty acids in serum reached 30%. In VLDL the ratios triglycerides/apolipoprotein B and triglycerides/phospholipids rose most after Lipofundin MCT and least after Lipofundin S. With Lipofundin MCT and Intralipid, surface components in low density lipoproteins (LDL) are lessened in relation to the internal components; this does not occur with Lipofundin S. High density lipoprotein (HDL) subfractions are influenced in identical directions by all fat emulsions with exception of a single increase of phospholipids in (HDL3) after Lipofundin MCT.
Decreased production of glutathione in patients with cirrhosis
Authors: BURGUNDER J.‐M. , LAUTERBURG B. H.
Published: March 2008

Abstract. Studies in animals have demonstrated the central role of the liver in regulating the circulating pool of glutathione (GSH). Most of the hepatic GSH production is released into blood and most of the circulating GSH originates in the liver. We have estimated the production of GSH in eight healthy volunteers and eight patients with cirrhosis by an analysis of the kinetics of plasma GSH. The basal plasma concentrations of free GSH were 9·3 ± 2·4 μM in healthy volunteers and 3·6 ± 1·1 μM in cirrhotics (P<0·001), and the concentrations of total GSH 16·6 ± 6·2 μM in control subjects and 7·1 ± 2·6 μM in cirrhotics (P<0·002). The concentration of GSH in the circulating pool depends on the input of GSH into this compartment and is inversely proportional to the volume of distribution of GSH (Vd) and to the fractional rate of elimination of GSH from plasma (kel). Assuming that the kinetics of endogenously produced and exogenously administered GSH are identical, Vd and kel can be calculated from the plasma concentration‐time curve of a single i.v. injection of GSH. Both Vd (0·100 ± 0·044 1 kg‐1 in controls and 0·131 ± 0·043 1 kg‐1 in cirrhotics) and kel (0·2718 ± 0·0555 min‐1 in controls and 0·2912 ± 0·0781 min‐1 in cirrhotics) were identical in the two groups. The estimated input of GSH into the circulation calculated as the product of the basal concentration of GSH, kel and Vd amounted to 392 ± 100 nmol min‐1 kg‐1 in control subjects and 242 ± 68 nmol min‐1 kg‐1 in cirrhotics (P<0·01). We conclude that the lower plasma concentrations of GSH in patients with cirrhosis are due to a decreased input of GSH into the circulation rather than an increased peripheral consumption of GSH. Most likely the defect reflects a decreased hepatic production of GSH and may increase the susceptibility of patients with cirrhosis to toxic insults.
Parathyroid hormone directly inhibits tubular reabsorption of bicarbonate in normocalcaemic rats with chronic hyperparathyroidism
Authors: JAEGER P. , JONES W. , KASHGARIAN M. , SEGRE G. V. , HAYSLETT J. P.
Published: March 2008

Abstract. The hypothesis that chronic metabolic acidosis encountered in some patients with primary hyperparathyrodism is due to inhibition of proximal HCO3 reabsorption has recently been challenged. Indeed, this action of parathyroid hormone (PTH) has only been observed in acute studies, whereas in animal models of chronic hyperparathyroidism a metabolic alkalosis has been induced, probably owing to the release of alkaline salts from bone tissue, and to the stimulation of tubular acid secretion by hypercalcaemia. Studies were, therefore, performed to determine the effect of PTH on the renal handling of HCO3 in an animal model in which changes in plasma calcium and phosphate, and nephrocalcinosis, all known to affect tubular acidification, did not occur. Thyroparathyroi‐dectomized (TPTX) rats were infused with synthetic bovine hormone fragment bPTH 1–34 via Alzet minipumps at the rate of 0·7 U h‐1 to simulate normal endogenous production of PTH (group I) and at the three‐fold higher rate of 2·1 U h‐1 (group II). In order to prevent changes in serum calcium and phosphate, and nephrocalcinosis, animals of group II were fed a Ca‐ and P‐free diet prior to TPTX (compared with a regular diet for group I) and both groups were treated with dichloromethylene‐diphosphonate (Cl2MDP, 10 mg kg‐1 day‐1) and a Ca‐free diet during PTH infusion. During the course of PTH infusion both groups of animals had stable and normal levels of plasma calcium and phosphate. Although systemic acid‐base parameters and urinary pH and HCO3 values were similar in animals with normal and elevated PTH levels under basal conditions, isovolaemic bicarbonate loading performed by peritoneal dialysis revealed a significant increase in urinary pH (7·37 ± 0·06 vs. 6·29 ± 0·29, P<0·005) and fractional bicarbonate excretion (0·52 ± 0·11 vs. 0·03 ± 0·02%, P<0·005) in the group with hyperparathyroidism. These data provide evidence that when chronically administered, parathyroid hormone directly inhibits tubular reabsorption of HCO3; they suggest that in clinical hyperparathyroidism HCO3 wasting results from excess secretion of the hormone.