bluuebunny/crossref_metadata_2025 huggingface dataset:
Dietary supplementation with very long‐chain n‐3 fatty acids in man decreases expression of the interleukin‐2 receptor (CD25) on mitogen‐stimulated lymphocytes from patients with inflammatory skin diseases
Authors: SØYLAND E. , LEA T. , SANDSTAD B. , DREVON A.
Published: March 2008

Abstract T‐cell activation and cytokine production play an important role in several chronic inflammatory diseases. Because n‐3 fatty acids exert beneficial effects on the clinical state of some of these diseases, we examined the effect of dietary supplementation of n‐3 fatty acids on T‐cell proliferation, expression of CD25 (interleukin‐2 receptor alpha‐chain), secretion of interleukin‐2, interleukin‐6 and tumour necrosis factor from T‐cells from patients with psoriasis and atopic dermatitis.

During 4 months, 21 patients supplied 6 g of highly concentrated ethyl esters of EPA and DHA in gelatin capsules daily to their diet. In the control group 20 patients supplied 6 g per day of corn oil in gelatin capsules to their diet.

Eicosapentaenoic acid (20:5, n‐3) of serum phospholipids increased from 14 (min 4‐max 42) to 81 (min 59‐max 144) mg l‐1 (P < 0·01) in patients with atopic dermatitis receiving n‐3 fatty acids, and from 25 (min 7‐max 66) to 74 (min 46‐max 142) mg l‐1 (P < 0·01) in patients with psoriasis, whereas docosahexaenoic acid (22:6, n‐3) increased from 65 (min 46‐max 120) to 92 (min 54‐max 121) mg l‐1 (P < 0·05) and from 81 (min 38‐max 122) to 92 (min 63‐max 169) mg l‐1 (NS) in atopic and psoriatic patients, respectively. The changes in the serum phospholipid fatty acid profile in the groups receiving n‐3 fatty acids, correlate to the dietary intake of corresponding fatty acids. There was no significant change in the fatty acid pattern of serum phospholipids in the corn oil group before and after supplementation.

Mitogen‐induced secretion of interleukin‐6 was significantly higher in patients with psoriasis compared to patients with atopic dermatitis, whereas the secretion of interleukin‐2, tumour necrosis factor, PHA‐induced T‐cell proliferation and expression of CD25 on lymphocytes were similar in the two groups of patients.

Patients receiving supplementation of n‐3 fatty acids decreased significantly the percentage of CD25 positive lymphocytes from 40·5 before start to 35·5 (P < 0·05) after the trial. The patients who received corn oil increased the level of tumour necrosis factor from 1095 pg ml‐1 before start to 1536 pg ml‐1 after the trial (P < 0·05). In conclusion, dietary intake of very long‐chain n‐3 fatty acids may suppress the expression of CD25 positive lymphocytes, which may partly account for the anti‐inflammatory effect exerted by these fatty acids.
Variable patterns of atrial natriuretic peptide secretion in man
Authors: NUGENT A. M. , ONUOHA G. N. , McENEANEY D. J. , STEELE I. C. , HUNTER S. J. , PRASANNA K. , CAMPBELL N. P. S. , SHAW C. , BUCHANAN K. D. , NICHOLLS D. P.
Published: March 2008

Abstract Peripheral circulating levels of atrial natriuretic peptide may exhibit short‐term variation compatible with a pulsatile pattern of secretion. We obtained samples every 2 min for 90 min from the antecubital vein of 16 patients with chronic cardiac failure and 13 controls. Overall levels were higher in the patients (median and quartiles 230 (125,325) vs. 26 (16,48) ng l‐1; P<0·001). In both groups there was considerable variability, with 10 (2–12) peaks, 9 (7–15) troughs (both defined as >2 SD from the mean) and 16 (13–18) pulses (defined by computer) during the sampling period in controls, and a similar number in patients. We then carried out simultaneous sampling in the pulmonary artery, femoral artery and peripheral vein in eight subjects with normal cardiac function and six patients with impaired function due to valvular heart disease. The pattern of variability was preserved in all three sites in both groups, suggesting intermittent secretion rather than variable breakdown of the peptide in the lung. No changes in right atrial pressure or heart rate were observed to coincide with the variations, but levels of the peptide in the pulmonary artery correlated with right atrial pressure in patients (r = 0·87; P<0·05). The mechanism of such periodicity and its pathophysiological importance remain unknown.
Phosphotyrosine protein profiles in monocytes after insulin and IGF‐1 stimulation
Authors: ZOPPINI G. , GALANTE P. , ZARDINI M. , MUGGEO M.
Published: March 2008

Abstract Mononuclear cells are largely used in clinical studies on insulin action because of their accessibility. Insulin acts in monocytes in different ways than it does in other cells, i.e. adipocytes and muscular cells. Therefore, it still remains unclear whether monocytes reflect the same changes that occur in insulin receptors at the level of the major insulin target tissues during different pathophysiologic states. We have studied the phosphotyrosine protein profiles in intact human monocytes after insulin and IGF‐1 stimulation with the aim of identifying substrate/s of these receptors and of comparing them to the substrates already described in major insulin target tissues. Mononuclear cells were prepared from peripheral blood by centrifugation on Ficoll Hypaque and by adhesion to tissue‐culture plates. Cell stimulation, lysis, immuno‐precipitation and western blotting were carried out following the protocol described by P. L. Rothenberg in 1991 and the immunoreactive proteins visualized on film by chemiluminescence. Insulin and IGF‐1 rapidly increased the tyrosine phosphorylation of the 95 Kdal β‐subunit of their own receptors. Under our experimental conditions insulin and IGF‐1 were not able to stimulate the phosphorylation of IRS‐1, a major substrate of the insulin receptor kinase.
Association between biosynthesis of nitric oxide and changes in immunological and vascular parameters in patients treated with interleukin‐2
Authors: MILES D. , THOMSEN L. , BALKWILL F. , THAVASU P. , MONCADA S.
Published: March 2008

Abstract Hypotension is a dose‐limiting side effect of interleukin‐2 (IL‐2) therapy. This may be due to increased biosynthesis of the potent vasodilator nitric oxide (NO) induced by cytokines such as tumour necrosis factor‐α (TNF‐α) and interferon‐γ (IFN‐γ), which are known to be generated during IL‐2 therapy. We describe the relationship between NO biosynthesis and changes in immunological and vascular parameters during IL‐2 therapy in 13 patients with metastatic cancer.

Plasma concentrations of neopterin and nitrite plus nitrate (NOx) were higher in cancer patients prior to treatment compared with normal subjects (neopterin; 10·8±1·4 vs. 2·0±0·4 ng ml‐1, P<0·001: NOx; 45±6 vs. 28±2 μM, P<0·005). Pretreatment TNF‐α and IFN‐γ plasma concentrations were not significantly different in cancer patients from those in controls. During infusion of IL‐2 (18 times 106 international units m‐2 per day for 5 days) these parameters increased, reaching maximal concentrations at day 3 for IFN‐γ and day 5 for TNF‐α, neopterin and NOx. The maximal induced NOx correlated with maximal TNF‐α (r = 0·60, P<0·04), IFN‐γ (r = 0·63, P<0·02) and neopterin (r = 0·66, P<0·01). As plasma NOx concentrations increased, systolic blood pressure fell, reaching a minimum at day 3 despite a continued rise in NOx concentrations. These changes were accompanied by a continuous increase in pulse rate throughout the infusion period. These findings indicate that induction of NO biosynthesis contributes to hypotension induced during IL‐2 therapy. Inhibitors of NO synthase may be useful in limiting toxicity, thus allowing administration of higher and possibly more efficacious doses of this cytokine in the treatment of cancer.
Neuropeptide Y and energy balance: one way ahead for the treatment of obesity?
Authors: DRYDEN S. , FRANKISH H. , WANG QIONG , WILLIAMS G.
Published: March 2008

Abstract Obesity is a vast and ever‐expanding problem in affluent societies, which we have so far failed to confront. Over 20% of Western European and North American adults are overweight to a degree which may potentially shorten their life expectancy. Obesity has well‐known associations with non‐insulin‐dependent diabetes (NIDDM), hypertension, dyslipidaemia and coronary heart disease, as well as less obvious links with diseases such as osteoarthrosis and various malignancies; it also causes considerable problems through reduced mobility and decreased quality of life. The overall financial burden of obesity is impossible to calculate precisely, but may account for 6–8% of total health‐care expenditure in North America [1] (similar estimates probably apply to Western Europe).

Obesity is difficult to treat and many patients remain obstinately overweight despite our best efforts. The available options range from behavioural therapy to gastrointestinal surgery and include numerous drugs designed to suppress appetite or increase energy expenditure. As in many other areas of medicine, the length and diversity of this list are reliable signs that effective treatment is still beyond our reach.

This article argues that new anti‐obesity drugs may emerge from recent advances in understanding the control of energy balance in rodents. The discussion is structured around neuropeptide Y (NPY), a major brain peptide which at present appears to be important in regulating energy balance and seems a promising candidate for therapeutic exploitation.
Lysine‐binding species of lipoprotein(a) in coronary artery disease
Authors: KARMANSKY I. , SHNAIDER H. , Palant A. , GRUENER N.
Published: March 2008

Abstract Elevated levels of plasma lipoprotein(a) [Lp(a)] have frequently been associated with coronary artery disease (CAD). Recently Lp(a) was fractionated into two species with different affinities for Lysine‐Sepharose. The influence of lysinebinding heterogeneity of Lp(a) on its cardiovascular pathogenicity has not previously been studied. The authors have determined plasma levels of total Lp(a), its lysinebinding [lys+] and unretained [lys—] species in 67 male CAD patients undergoing cardiac catheterization. Forty‐three patients have severe CAD (two‐ or three‐vessel disease) and 24 patients have less pronounced CAD (one‐vessel disease or less than 50% narrowing of coronary vessels). All patients were ranked in order of their Lp(a) levels and then grouped into quartiles. The prevalence of severe CAD was significantly higher in the upper Lp(a) quartile as compared with the other three quartiles (odds ratio 10·5; chi‐square 11·2; P=0·0008). Similar results were obtained when the same analysis was carried out for [lys +] and [lys—] species of Lp(a) (odds ratio 11·52 and 3·3, respectively; chi‐squre 12·3 and 4·34, respectively; P=0·0004 and 0·037, respectively). Thus, measurement of either species of Lp(a) does not provide any additional improvement in the prediction of CAD as compared to the estimation of total Lp(a) levels.
The lymphocyte Na+/H+ antiport: activation in primary hypertension and during chronic NaCl‐loading
Authors: GÖBEL B. O. , HOFFMANN G. , RUPPERT M. , STUMPE K. O. , VETTER H. , SIFFERT W. , DÜSING R.
Published: March 2008

Abstract. Increased activity of the Na+/H+ antiport may be a major abnormality in essential hypertension. The activity of this transport system was investigated in lymphocytes from 13 patients with untreated essential hypertension (Ht) and 13 normotensive control subjects (Nt) on an ad libitum (130–170 mmol d‐1) NaCl intake. Furthermore, the effects of different states of NaCl balance on lymphocyte Na+/H+ antiport were evaluated in two groups of Nt volunteers receiving 20 vs. 300 mmol d‐1 (n= 8) and 85 vs. 200 mmol d‐1 (n= 14) of NaCl for 1 week each and in seven Ht patients (20 vs. 300 mmol NaCl d‐1 for 1 week each). Additionally, during the 20 and 300 mmol/d NaCl intake red blood cell membrane transport was studied in eight subjects. For the determination of lymphocyte antiport activity, cells were loaded with the cytosolic pH (pHi) indicator bis‐carboxyethyl carboxyfluorescein (BCECF‐AM) and acidified by addition of different amounts of Na+‐propionate (5–40 mM). Initial pHi‐recovery was taken as the activity of the antiport system and plotted against pHi‐values after acidification. Non‐linear regression analysis yielded higher ’apparent’ maximal transport rates in Ht than Nt (Nt: 2·00 pL 0·22; Ht: (3·81 pL 0·59)·10‐3 s‐1; P < 0·025). In contrast, baseline pHi‐values and pHi‐values at half‐maximal activity (pK) were identical in Nt and Ht. In normotensive control subjects on an NaCl intake of 20, 85, 200 and 300 mmol d‐1 for 7 d, ’apparent’ maximal transport rates averaged 2.75 0·20, 2·89 0·17, 2·81 ± 0·18 and (3·62 ± 0·25) · 10‐3 s‐1, respectively. Thus, antiport activity was significantly (P < 0·05) stimulated on the 300 mmol d‐1 intake as compared to the three other NaCl intakes. The extreme intakes of NaCl (20 vs. 300 mmol d‐1) in normotensive volunteers did not affect the erythrocyte Na+/K+ pump, Na+/K+ cotransport and Na+/Li+ countertransport. Our study supports the concept that a group of patients with primary hypertension exhibit an activated Na+/H+ antiport. Furthermore, our data demonstrate that a chronic high intake of NaCl is associated with an increase in lymphocyte antiport activity towards the high values observed in primary hypertension.
Abdominal rubber drain piece aggravates intra‐abdominal sepsis in the rat
Authors: GUO W. , SOLTESZ V. , DING JIN WEN , WILLÉN R. , LIU XIAOYING , ANDERSSON R. , BENGMARK S.
Published: March 2008

Abstract. Biomaterials in the peritoneal cavity disrupt the physiology of the host and may cause bacterial translocation. The current study was performed to determine whether biomaterials exacerbate intraabdominal infections. Adult male rats were divided into four groups: group 1, celiotomy + intraperitoneal (i.p.) saline; group 2, celiotomy + i.p. Escherichia coli (3 times 108 cfu); group 3, i.p. rubber + i.p. saline; and group 4, i.p. rubber + i.p. E. coli(3 times 108 cfu). Twelve h after the challenge, enteric bacterial translocation, bacterial population levels in the cecum and serum levels of IL‐6 and TNF were measured. Bacterial translocation to mesenteric lymph nodes and the liver was observed in animals from groups 2 and 3, but significantly increased in group 4 with a concomitant elevation of serum levels of TNF and IL‐6, as compared with group 1. Histological examination revealed a more pronounced inflammatory reaction in the peritoneum and distal ileum in group 4 than in groups 2 and 3. These results suggest that the presence of rubbers in the peritoneal cavity aggravates intraabdominal sepsis.
Inter‐relations between the calcium set‐points of Parfitt and Brown in primary hyperparathyroidism: a sequential citrate and calcium clamp study
Authors: SCHWARZ P. , SØRENSEN H. A. , TRANSBØL I. , Mineral Metabolic Research Group
Published: March 2008

Abstract. The objective of the present study was to compare the calcium set‐points of E. M. Brown and A. M. Parfitt obtained by sequential citrate and calcium clamp in patients with primary hyperparathyroidism and healthy controls. Twenty‐six patients with primary hyperparathyroidism were investigated and compared to 22 healthy volunteers. All participants were investigated by sequential calcium lowering and raising comprising the following four phases: Phase (1) blood ionized calcium lowering of about 0·20 mmol l‐1; phase (2) steady‐state (relative) hypocalcaemia of blood ionized calcium 0·20 mmol l‐1 below baseline; phase (3) blood ionized calcium is raised to about 0·20 mmol l‐1 above baseline; and phase (4) (relative) hypercalcaemia of blood ionized calcium 0·20 mmol l‐1 above baseline. Serum parathyroid hormone (1–84) was measured by an immunoradiometric assay. Blood ionized calcium was measured by a calcium selective electrode. We found the calcium set‐points of Parfitt to be 1·42 mmol l‐1 (SD 0·12, n= 52) vs. 1·25 mmol l‐1 (SD 0·04, n= 44) in patients and controls, respectively (P < 0·001). The calcium set‐points of Brown were 1·32 mmol l‐1 (SD 0·10, n= 26) vs. 1·13 mmol l‐1 (SD 0·04, n= 22), respectively (P < 0·001). By comparing the calcium set‐points of Parfitt and Brown, a strikingly good correlation was observed, in patients (r= 0·91, P < 0·001) and in controls (r= 0·85, P < 0·001). We demonstrate in this paper in vivo that Brown's and Parfitt's calcium set‐points are raised in primary hyperparathyroidism and return to normal following parathyroidectomy. The values for Brown's and Parfitt's calcium set‐points are significantly different, but strikingly well correlated, supporting the view that Brown and Parfitt describe two different points on the same sigmoidal curve, corresponding to 50% and about 85% inhibition of PTH maximum, respectively. The mathematical form of the sigmoidal curve between blood ionized calcium and parathyroid hormone is very similar in primary hyperparathyroidism and normal humans.
Cognitive brain function in non‐demented patients with low‐grade and high‐grade carotid artery stenosis
Authors: MADL C. , GRIMM G. , KRAMER L. , KOPPENSTEINER R. , HIRSCHL M. , YEGANEHFAR W. , HIRSCHL M. M. , UGURLUOGLU A. , SCHNEIDER B. , EHRINGER H.
Published: March 2008

Abstract. Atherosclerotic stenosis of the carotid arteries decreases cerebral flow volume and perfusion, and may result in brain dysfunction. We studied the relationship between the degree of carotid artery stenosis and cognitive brain function in non‐demented patients. Cognitive brain function was assessed in 76 patients with carotid artery stenosis (38 patients with low‐grade stenosis of 50% or less, and 38 patients with high‐grade stenosis of 75% or more) by recording of cognitive P300 auditory evoked potentials and trail‐making test. Results were compared to 70 age‐matched healthy subjects. The P300 peak latency was prolonged in patients with high‐grade carotid artery stenosis as compared to patients with low‐grade stenosis (403 vs. 371 ms, P < 0·01, vertex; 400 vs. 370 ms, P < 0·01, frontal; means). Analysis of variance revealed that the degree of carotid artery stenosis is an independent predictor of prolonged P300 peak latency (P= 0·0001). P300 amplitude (12 vs. 15 μ V, vertex; 13 vs. 15 μ V, frontal, NS) and trailmaking test (60 vs. 54 s; NS) tended to be worse in the high‐grade stenosis group. There was no difference in cognitive brain function between patients with low‐grade stenosis and age‐matched healthy subjects. Confirmed on sensitive cognitive P300 measurements, we conclude that (a) cognitive brain function is impaired in non‐demented patients with high‐grade carotid artery stenosis but unaffected in low‐grade stenosis; and (b) cognitive brain dysfunction is directly related to the degree of carotid artery stenosis.
A 5‐year controlled randomized study of prevention of postmenopausal trabecular bone loss with nasal salmon calcitonin and calcium
Authors: REGINSTER J. Y. , MEURMANS L. , DEROISY R. , JUPSIN I. , BIQUET I. , ALBERT A. , FRANCHIMONT P.
Published: March 2008

Abstract. The aim of this paper was to evaluate the long‐term (5 years) efficacy of nasal salmon calcitonin in prevention of trabecular postmenopausal bone loss, which was a follow‐up of a previously published study (3 years); a randomized, controlled group comparison. One hundred healthy postmenopausal women were randomly chosen from those (186) having completed the 3 year protocol. The 100 women were allocated to an additional 2 year period (total of 5 years) of treatment with either 500 mg d‐1, 5 days week‐1 of calcium or the same amount of calcium plus 50 IU d‐1, 5 days per week of nasal salmon calcitonin, 87 (87%) women complied with the protocol throughout. The main outcome measures were the bone mineral density of the lumbar spine (1‐BMD) (DPA) and biochemical parameters reflecting bone turnover (serum alkaline phosphatases, urinary calcium/creatinine and hydroxyproline/creatinine ratios). The women receiving calcium alone presented a significant decrease in 1‐BMD after 6 months [– 1·6 (0·5)%] [mean(SEM)] (P < 0·01) and this decrease remained significant after 36 months [– 6·1(0·8)%] (P < 0·01) and until the end of the trial [– 6·6(1·0)% at t60] (P < 0·01). In women receiving calcium and calcitonin, 1‐BMD significantly increased after 36 months [+ 2(0·7%] (P < 0·01) and 42 months [+ 2·5(0·7)%] (P < 0·01) and was unchanged at the other times of investigation [+ 1·1(1·1)% at t60] (NS). The evolution of BMD in the two groups was highly significantly different (P < 0·001) since the sixth month of the study and remained so until the end of the study. No differences were observed in the biochemical parameters reflecting bone turnover. Nasal administration of salmon calcitonin, using a low‐dose (50 IU d‐1), intermittent (5 days week‐1) regimen, may totally prevent postmenopausal bone loss, at the level of the lumbar spine, for at least 5 years, if the treatment is continued for this duration. It is not clear whether the results observed during the fourth and fifth years are fully attributable to calcitonin or if calcium by itself plays also a protective role against trabecular bone loss.
Kinetics of circulating hyaluronan in humans
Authors: LEBEL L. , GABRIELSSON J. , LAURENT T. C. , GERDIN B.
Published: March 2008

Abstract The elimination of intravenously injected hyaluronan (HA) from the blood was investigated in 12 healthy volunteers. Three consecutive 30 min infusions of HA were given, separated by 90 min washout periods. Blood samples were taken before, during and after each infusion and the plasma HA concentration was determined. The deposition of HA was modelled according to a Michaelis–Menten kinetic model which included natural synthesis of HA. Km and Vmax was estimated to 0·34 ± 0·13 μgml‐1 and 3·48 ± 0·97/μmin‐1kg‐1 b.w., respectively. The endogenous input was calculated to be 24 ± 11 μg min‐1 and was found to correlate to the age of the subjects (P < 0·05). As the baseline HA concentration was 0·031 ± 0·21 μg ml‐1, the rate of elimination was linear in the normal concentration range. The calculated Vd was about 75% higher than a weight‐estimated plasma volume. The total amount of HA excreted by the kidneys during the study period was 394 ± 77 μg, which corresponded to approximately 1·7% of the total input of HA into the circulation during the experiment.
Erythrocyte Na+‐H+ exchanger and Na+‐Li+ countertransport activity in primary aldosteronism
Authors: DELVA P. , PASTORI C. , DEGAN M. , MONTESI G. , BASSI A. , LECHI A.
Published: March 2008

Abstract. Several authors have described increased Na‐H exchanger activity in essential hypertension but no data are available in secondary forms of hypertension such as primary aldosteronism. We measured Na‐H exchanger kinetics together with Na‐Li countertransport Vmax in the erythrocytes of eight patients with primary aldosteronism and in 15 normotensive control subjects. Plasma aldosterone, plasma renin and plasma potassium were also evaluated. Na‐H exchanger Vmax appear to be increased in patients with primary aldosteronism and Hill's n, an index of co‐operativity amongst intracellular proton binding sites, was significantly lower in patients than in controls. No statistically significant differences were found between affinity for intracellular protons (K50%) and for Na‐Li countertransport Vmax between the two groups studied. We were unable to find any correlations between Na‐H exchanger Vmax and Na‐Li countertransport Vmax in the two groups considered as a whole. From the present data Na‐H exchanger overactivity would not appear to be a specific feature of essential hypertension but seems to be characteristic in patients with primary aldosteronism.
Increase of tumour necrosis factor α synthesis and gene expression in peripheral blood mononuclear cells of children with idiopathic nephrotic syndrome
Authors: BUSTOS C. , GONZÁLEZ E. , MULEY R. , ALONSO J. L. , EGIDO J.
Published: March 2008

Abstract. The pathogenesis of idiopathic nephrotic syndrome (minimal change nephropathy and its variants) is not completely understood. In recent years it has been speculated that a cytokine released by circulating blood mononuclear cells could alter the permeability of the glomerular capillary wall. In this study we have explored the potential participation of tumour necrosis factor α (TNFα), a cytokine mainly produced by monocytes, in 25 children with idiopathic nephrotic syndrome. TNFα was determined by cytotoxicity bioassay in the L‐929 cell line and by double antibody/RIA. Patients in activity had higher serum TNFα levels and TNFα production by monocytes than patients in remission and controls. TNFα mRNA expression in blood mononuclear cells was analysed by Northern blot. The TNFα mRNA levels in patients in activity were increased compared to controls and to patients in remission. No significant differences in IL‐1β and IL‐6 synthesis were found between patients and controls. Our results suggest that TNFα, but not other cytokines such as IL‐1β and IL‐6, could play a role in the pathogenesis of the proteinuria in idiopathic nephrotic syndrome.
Time course of haemodynamic changes after maximal exercise
Authors: ISEA J. E. , PIEPOLI M. , ADAMOPOULOS S. , PANNARALE G. , SLEIGHT P. , COATS A. J. S.
Published: March 2008

Abstract. The haemodynamic changes during 4 h following maximal upright bicycle exercise were evaluated in six normals in a randomized controlled crossover design. Total peripheral resistance was reduced to 2 h (‐6·7 mmHgmin l‐1, P < 0·05); exercising and non‐exercising vascular beds were vasodilated for 2h (‐24·1 and ‐23·8 mmHg min ml‐1 100ml‐1 tissue, respectively, P < 0·05), associated with reductions in systolic (‐5·8 mmHg, P < 0·05) and diastolic pressure (‐8·3mmHg, P < 0·05). Rise in cardiac index for 1 h (+0·51min‐1 m‐2, P < 0·05) was accounted for by an elevated heart rate (+14·4 beats min‐1, P < 0·01) as stroke volume was unchanged. Body temperature was elevated until 40min (+0·20°C, P < 0·05). The return of all haemodynamic variables to control by 3h suggests a 3 h limit for a hypotensive effect of exercise. Rise in body temperature is not the only factor responsible for the hypotension.
A study of factors governing fluid filtration in the diabetic foot
Authors: RAYMAN G. , WILLIAMS S. A. , GAMBLE J. , TOOKE J. E.
Published: March 2008

Abstract. The effect of lowering the foot on the factors governing fluid filtration in the foot were studied in 12 male insulin‐dependent diabetic subjects and 10 controls. Toe skin blood flow, measured by laser Doppler flowmetry, was significantly higher during dependency in the diabetic group. In the control subjects, the colloid osmotic pressure of venous blood sampled from the foot rose to 47·7 mmHg (range 45·1–53·8) after 50 min of foot dependency. In the diabetic group, colloid osmotic pressure failed to rise to the same extent (median 36·7 mmHg; range 28·6–43·0; P < 0·001). Capillary pressure, measured directly by the Landis microinjection technique, was significantly higher in the diabetic group (85·3±1·7 (n= 6) vs. 92·2±4·6 cm H2O (n= 6); P < 0·007), as was foot swelling rate determined by mercury strain gauge plethysmography (0·069±0·022 vs. 0·099±0·025 ml min‐1 100ml‐1; P < 0·02). These results suggest an impairment of the oedema‐preventing mechanisms in diabetic subjects which may contribute to the risks of ulceration in the diabetic foot.
Local serum application: restoration of sufficient host defense in human peritonitis
Authors: BILLING A. G. , FRÖHLICH D. , KONECNY G. , SCHILDBERG F. W. , MACHLEIDT W. , FRITZ H. , JOCHUM M.
Published: March 2008

Abstract. Intra‐abdominal host defense in human peritonitis is hampered by a severe dysfunction of phagocytosis due to an almost complete breakdown of bacteria opsonization. This defect relates to some opsonin consumption, but mainly to proteolytic and oxidative opsonin destruction. To restore and protect intact opsonins we have developed a clinical approach of intra‐operative peritoneal serum application. In a prospective, controlled, and randomized study of 30 patients with generalized peritonitis we have investigated the impact of this adjuvant therapy on biochemical parameters and clinical features. Serum application induced a rise in opsonin concentration and, even more pronounced, opsonin function (P < 0·01) of several hours' duration, leading to a distinct improvement of bacteria elimination. In addition, α1‐proteinase inhibitor (α1‐P)I levels were significantly increased after 1 h (P < 0·05) in the treatment group.

The follow‐up by APACHE II scoring indicated an improvement in the therapy group over the whole observation period of 14 days. Lethality in the therapy group was 33% compared to 53% in controls. These results indicate that the intra‐operative restoration of physiologic intra‐abdominal milieu can improve bacteria opsonization and elimination, thus contributing to a favourable clinical course in abdominal sepsis.
Serum levels of interleukin‐6 and tumour‐necrosis‐factor‐alpha are not correlated to disease activity in patients with rheumatoid arthritis after treatment with low‐dose methotrexate
Authors: WASCHER T. C. , HERMANN J. , BREZINSCHEK R. , BREZINSCHEK H. P. , WILDERS‐TRUSCHNIG M. , RAINER F. , KREJS G. J.
Published: March 2008

Abstract. Cytokines are major mediators of inflammatory responses in rheumatoid arthritis. Some of them have been shown to correlate with the disease activity and thus are proposed to be used for monitoring patients. Therefore the effects of a low‐dose therapy with methotrexate on serum concentrations of interleukin‐6 (IL‐6) and tumour‐necrosis‐factor‐alpha (TNF‐α) were examined in eight patients with seropositive rheumatoid arthritis. Serum levels of IL‐6 and TNF‐α were significantly elevated in patients compared to healthy controls. Before the onset of MTX treatment IL‐6 concentrations were correlated to the c‐reactive protein (P < 0·05) but the correlation was abolished after treatment. For TNF‐α no correlations neither before nor after treatment were observed. Both cytokines remained substantially elevated after MTX treatment despite a clear reduction in disease activity. Thus we suggest that one of the effects of MTX might be the inhibition of some of the actions of IL‐6 and TNF‐α.
Nitric oxide and the pathogenesis of heart muscle disease
Authors: de BELDER A. J. , RADOMSKI M. W. , MARTIN J. F. , MONCADA S.
Published: March 2008

The nature of the impaired cardiac performance seen in septic shock, acute myocarditis, dilated cardiomyo‐pathy, heart transplant rejection and immunotherapy cardiomyopathy is not well understood. The current treatment options for these conditions are limited by a lack of understanding of the underlying pathogenesis, and the management of patients with these conditions is centred on the consequences of the myocardial damage rather than the causes. However, recent research has opened new doors to the comprehension of the cellular mechanisms underlying these myocardial disorders, which may lead to more specific treatment. In this review, we present evidence for the hypothesis that myocardial production of nitric oxide (NO) is a final common pathway of several different immunological challenges and accounts for, at least in part, the negative inotropism associated with these heart muscle disorders.
Effects of chronic treatment with a nitric oxide donor on nerve conduction abnormalities and endoneurial blood flow in streptozotocin‐diabetic rats
Authors: CAMERON N. E. , COTTER M. A.
Published: March 2008

Abstract. This study examined the ability of nitrova‐sodilator treatment with isosorbide dinitrate to prevent the development of reduced nerve conduction velocity and nutritive blood flow in streptozotocin‐induced diabetes mellitus in rats. Two month untreated diabetes caused approximately 23% and 13% reductions in sciatic motor and saphenous nerve sensory conduction velocity (P < 0.001). Isosorbide dinitrate treatment provided 64.6 and 67.6% protection for motor and sensory nerves, respectively (P < 0.01). Sciatic endoneurial nutritive blood flow was measured by microelectrode polarography and a hydrogen clearance technique. After 1 month untreated diabetes, flow was reduced by 41.9% (P < 0.001). Isosorbide dinitrate treatment for 1 month in non‐diabetic and diabetic rats significantly increased blood flow (P < 0.01). When between‐group variations in blood pressure were taken into account, vascular conductance increased by 29% and 31% in non‐diabetic and diabetic rats, respectively (P < 0.01). Thus, nitrovasodilator treatment improves nerve perfusion and function in experimental diabetes, probably by compensating for reduced endothelium‐derived nitric oxide release or action.
δ‐Aminolaevulinic acid dehydratase as an index of lead toxicity. Time for a reappraisal?
Authors: CHALEVELAKIS G. , BOURONIKOU H. , YALOURIS A.G. , ECONOMOPOULOS TH. , ATHANASELIS S. , RAPTIS S.
Published: March 2008

Abstract. δ‐Aminolaevulinic acid dehydratase activity is traditionally accepted as the most sensitive measurable biological index of lead toxicity. We have measured δ‐aminolaevulinic acid dehydratase activity and blood lead concentration in 47 healthy controls (A), 42 iron deficient patients (B) and 38 occupationally exposed to lead subjects (C). Blood lead levels [x (SD)] did not differ between groups A and B [0.51 (0.21) and 0.43 (019) μmol L‐1, respectively] while those of group C [2.28 (0.56) μmol L‐1 were significantly higher (P < 0.001) as compared to the controls. δ‐Aminolae‐vulinic acid dehydratase activity [x (SD)] was significantly increased [3599 (1909) μmol L‐1 h‐1] in group B and decreased in group C [1052 (532) μmol L‐1 h‐1] as compared to the controls [2034 (446) μmol L‐1 h‐1] (P < 0.001). There was a significantly negative correlation of logarithm of δ‐aminolaevulinic acid dehydratase with lead in both groups B (P < 0.05) and C (P < 0.001) but not in group A (P= 0.1). δ‐Amino‐laevulinic acid dehydratase activity had a high specificity (100%) but a low sensitivity (37%) as an index of toxic lead exposure. According to our data the value of δ‐aminolaevulinic acid dehydratase measurement in the diagnosis of lead intoxication is doubtful in cases with low blood lead levels, while in the presence of iron deficiency its reliability is further reduced, since low blood lead levels may be falsely predicted. δ‐Amino‐laevulinic acid dehydratase activity should be restricted only to monitoring cases with moderate or severe lead poisoning.
Integrins: structure, biological functions and relevance in viral chronic hepatitis
Authors: GARCIA‐MONZON C. , GARCIA‐BUEY L. , MAJANO P. L. , MORENO‐OTERO R.
Published: March 2008

The integrin family represents the largest group of cell surface proteins that mediate cell adhesion in humans [1,2]. Adhesion is of fundamental importance to a cell as it provides anchorage, cues for migration and a signal for growth and differentiation. There are two different types of cell adhesion: cell‐extracellular matrix adhesion and cell‐cell adhesion. Integrins appear to be the major receptors by which cells attach to extracellular matrices. In addition, some integrins also mediate important cell‐cell adhesion events. The term ‘integrin’ was coined in order to signify the presumed role of these proteins in integrating the intracellular cytoskeleton with the extracellular matrix.
Effects of epidermal growth factor (EGF), platelet‐derived growth factor (PDGF) and fibroblast growth factor (FGF) on human adipocyte development and function
Authors: HAUNER H. , ROHRIG K. , PETRUSCHKE T.
Published: March 2008

Abstract. We investigated the effects of epidermal growth factor (EGF), platelet‐derived growth factor (PDGF) and fibroblast growth factor (FGF) on the differentiation of human adipocyte precursor cells and some metabolic aspects of newly formed fat cells kept in primary culture. Exposure of stromal cells from human adipose tissue to EGF (0.01–100 ng mL‐1) resulted in a dose‐ and time‐dependent decrease in the number of developing fat cells and the activity of glycerol‐3‐phosphate dehydrogenase (GPDH), a marker of adipose differentiation. Continuous presence of EGF completely blocked lipid accumulation with a ED50 in the range of 0.2ng mL‐1. This inhibitory action of EGF was associated with a potent stimulation of cell proliferation, up to 8‐fold compared with cultures in the absence of EGF. PDGF (0.1–50ngmL‐1) and FGF (0.1–100ng mL‐1) provoked a less marked suppression of GPDH activities which was significant at concentrations of 10 ng mL‐1 and higher. A 12 day exposure to EGF of differentiated cells was followed by a suppression of GPDH and, again, a significant increase in cell number. Concomitantly, a distinct loss of cellular lipids was observed in the newly formed adipocytes. This effect could be partly explained by a stimulation of lipolysis, since EGF caused an increase of glycerol in the culture medium. Addition of PDGF or FGF to newly developed fat cells had no effect on lipolysis but, at higher concentrations, also decreased GPDH activity. These findings suggest that EGF is a potent inhibitor of adipose cell differentiation at physiological concentrations, and may be involved in the control of human adipose tissue development and function.
Exhaled nitric oxide concentration and amniotic fluid nitrite concentration during pregnancy
Authors: MORRIS N. H. , CARROLL S. , NICOLAIDES K. H. , STEER P. J. , WARREN J. B.
Published: March 2008

Abstract. We have assessed fetal and maternal nitric oxide (NO) production in pregnancy. Exhaled NO and amniotic fluid nitrite concentrations were measured by chemiluminescence between 10 and 42 weeks of pregnancy. Exhaled NO concentrations did not alter significantly during gestation. In contrast, there was a significant change in mean amniotic fluid nitrite concentration in late pregnancy (P < 0.001). The finding of decreased amniotic nitrite concentrations after 37 weeks of gestation support the hypothesis that reduced NO production may contribute to increased uterine activity in late pregnancy.
The lipoprotein composition of plasma and ascitic fluid in liver cirrhosis
Authors: ZAMBON S. , ORLANDO R. , SARTORE G. , BASSIx A. , MANZATO E. , CREPALDI G.
Published: March 2008

Abstract. Lipoprotein particles were examined in plasma and ascitic fluid from nine patients (5 males and 4 females) with liver cirrhosis and in plasma from nine control subjects. LDL and HDL fractions were isolated by ultracentrifugation under rate flotation conditions in a zonal rotor. LDL size was analysed by non‐denaturing polyacrylamide gradient gel elec‐trophoresis. Plasma lipids in cirrhotic patients were markedly reduced compared to controls. Free cholesterol represented 45.3% of the total cholesterol in plasma and 70.4% of the total cholesterol in the ascitic fluid. The total cholesterol‐triglyceride ratio was three times higher in the plasma than in the ascitic fluid of cirrhotic patients. The LDL particles had the same flotation properties in plasma from cirrhotic patients as in that from controls. In cirrhotic patients the IDL concentration was higher than that in controls. In ascitic fluid the LDL particles had a higher flotation rate than in the plasma. The LDL diameter as measured by gradient gel electrophoresis was similar in both plasma and ascitic fluid of the cirrhotic patients as well as in the plasma of controls. In plasma and ascitic fluid of cirrhotic patients only a single HDL subclass (HDL1) could be identified. HDL1 particles had a higher flotation rate than normal HDL particles. The plasma levels of all the apoproteins were reduced in cirrhotic subjects compared to controls, but to a variable degree; while apo CII level in cirrhosis represented only 9% of the control level, the apo E level represented 77% of the control level. Lipoprotein particles from the plasma of patients with liver cirrhosis differed in several respects not only from normal particles but also from particles isolated from ascitic fluid in the same patient. These differences may prove useful for improving our understanding of normal lipoprotein metabolism and of the mechanisms involved in ascitic fluid formation.
Lipid peroxidation and susceptibility of low‐density lipoprotein to in vitro oxidation in hyperhomocysteinaemia
Authors: BLOM H. J. , KLEINVELD H. A. , BOERS G. H. J. , DEMACKER P. N. M. , HAK‐LEMMERS H. L. M. , POELE‐POTHOFF M. T. W. B. TE , TRIJBELS J. M. F.
Published: March 2008

Abstract. The pathobiochemical mechanism of arteriosclerosis in hyperhomocysteinaemia has not yet been elucidated. In vitro studies have shown that the cytotoxic properties of homocysteine can be ascribed to its generation of reactive oxygen species. We studied lipid peroxidation, both in vivo and in vitro, in 10 homozygous cystathionine synthase‐deficient (CSD) patients and in a control group of 10 healthy subjects of comparable age and sex. The susceptibility of low‐density lipoprotein (LDL) from hyperhomo‐cysteinaemic patients to oxidation was determined in vitro by continuously measuring the conjugated diene production induced by incubation with copper ions. Oxidation resistance (expressed as lag time), maximal oxidation rate, and extent of oxidation (expressed as total diene production) of LDL from CSD patients were not significantly different from those of LDL from controls. Furthermore, the time needed to reach maximal diene production, i.e. t(max), was similar for LDL from patients and controls. In addition, the vitamin E concentrations in LDL of CSD patients and controls were similar. The mean concentration (± SD) of plasma thiobarbituric acid reactive substances (TBARS), an indicator of in vivo lipid peroxidation, was 2.2 ± 0.7 μmol L‐1 in CSD patients, a lower value than that measured in the matched controls (50± 2.0 μmol L‐1). Investigation of in vivo and in vitro parameters of lipid peroxidation shows that the increased risk of arteriosclerosis in hyperhomocysteinaemia is unlikely to be due to increased lipid peroxidation.
Hormonal and renal responses to neutral endopeptidase inhibition in normal humans on a low and on a high sodium intake
Authors: SAGNELLA G. A. , MARKANDU N. D. , BUCKLEY M. G. , MILLER M. A. , BLACKWOOD A. , SINGER D. R. J. , MACGREGOR G. A.
Published: March 2008

Abstract. Hormonal and renal effects of candoxatril, a neutral endopeptidase 24.11 inhibitor, were investigated in eight subjects equilibrated on a low sodium diet (10 mmol sodium per day) and a high sodium (350 mmol per day) diet. After candoxatril treatment, plasma ANP increased to a maximum at 2–4 h and declined to baseline within 24 h. The increases were relatively greater on the high sodium diet, which was also associated with increases in urinary sodium, with highest values at 4h. On the low sodium diet, the magnitude of the changes was significantly lower (24 h cumulative sodium excretion was 11.4± 5.5 mmol on the low sodium diet and 73.1± 25.6 mmol on the high sodium diet; P < 0.01). There were no significant effects on urinary potassium excretion, creatinine clearance or haematocrit. After candoxatril treatment there were reductions in PRA, especially on the low sodium diet. On either diet there were no effects on systemic blood pressure. These results demonstrate that dietary sodium intake is an important determinant of the renal and hormonal responses to neutral endopeptidase inhibition.
Prolonged consumption of moderate doses of alcohol and in vitro gastro‐duodenal and ileal contractility in the rat
Authors: PALASCIANO G. , PORTINCASA P. , CIAULA A. DI , PALMIERI V.
Published: March 2008

Abstract. The effects of chronic feeding with moderate doses of ethanol (3% vol/vol in drinking water for 8 weeks), which do not induce tolerance, dependence and withdrawal, on the contractility of gastric, duodenal and ileal strips from rats were investigated. Only 50% of ethanol‐treated specimens (as compared to 100% of saccharose‐fed controls) exhibited antral phasic contractions (frequency decreased by 31% and 27% in the antrum and duodenum, respectively; P < 0.03 vs. controls). The depolarizing agent potassium chloride (KG, 80 mm) produced less peak active tension in the fundus of ethanol‐fed rats (P < 0.01). In alcoholic rats the sensitivity of the antrum to acetyl‐choline was fourfold less than that of control specimens. It is concluded that, in the rat, moderate doses of ethanol given chronically impair both spontaneous and tonic contractility of the stomach and duodenal muscle without affecting ileal contraction. It is possible that motility defects in the gut exposed to ethanol concentrations which do not cause tolerance, dependence or withdrawal in the rat may be due to a local rather than a systemic effect on the smooth muscle.
Radioiodine therapy of Graves' hyperthyroidism: standard vs. calculated 131 iodine activity*. Results from a prospective, randomized, multicentre study
Authors: PETERS H. , FISCHER C. , BOGNER U. , REINERS C. , SCHLEUSENER H.
Published: March 2008

Abstract. The present prospective, randomized, multicentre study was performed to directly compare for the first time the effectiveness of a standard activity of 555 MBq 131 iodine vs. an activity calculated to deliver 100 Gy for treatment of Graves' thyro‐toxicosis. Therapeutic success was defined as the elimination of hyperthyroidism 6 months after radio‐iodine application (range 4.5–8 months). A success rate of more than 90% in eliminating hyperthyroidism was reported for both approaches, but only in retrospective investigations. Investigated prospec‐tively, hyperthyroidism was eliminated in only 71% of the patients receiving standard activity (70/98) and 58% of those randomized for calculated activity (62/107). In the patients with standard activity, therapeutic success was inversely related to thyroid size. The rate was 100% for thyroid volumes ≤15 mL, 95% for 16–30 mL, 68% for 31–45 mL, 44% for 46–50 mL, 20% for 61–75 mL and 25% for ≥75 mL. In those patients with an activity calculated to deliver 100 Gy (except in those with a volume ≥15 mL) this size/outcome dependency was almost compensated. The rates were 86%, 65%, 45%, 61%, 41% and 45%, respectively. Furthermore, detailed statistical analysis revealed a strong correlation between the success of therapy and the radiation dose actually absorbed by the thyroid. The rate was 11 % for a target dose of 50Gy, 50% for 100 Gy, 67% for 150Gy, 80 % for 200 Gy, 84 % for 250 Gy, 88 % for 300 Gy, 90 % for 350 Gy and 93% for 400 Gy. Based on the results obtained in the present study, we strongly recommend individual calculation of the131 iodine activity to be administered for treatment of Graves' hyperthyroidism. However, the target dose should be in the range of 200Gy.
Veno‐arterial carbon dioxide and pH gradients and survival in critical illness
Authors: LIND L.
Published: March 2008

Abstract. Recent studies have shown that the veno‐arterial gradient for carbon dioxide (dVVApCO2) is increased in the case of low cardiac index (CI). In order to further investigate this matter 220 haemody‐namic measurements from 34 patients with septic shock and from 28 patients in the post‐operative state without sepsis were evaluated. The arterio‐venous gradient for pH (dAVVpH) was also evaluated. CI was found to be inversely correlated to both dVVApCO2 and dAVVpH when the two groups of patients were analysed separately (r= ‐0.76 and r= ‐0.78, P< 0.001 for the relationship between CI and dVVApCO2, r = ‐0.58 and r = ‐0.69 P<0.001 for the relationship between CI and dAVVpH). When volume loading over 2 h was used to increase CI, 58–66% of_the patients in the two groups showed a decline in dVVApCO2 > 10% when CI was increased by > 10%. The corresponding values for a reduction in dAVVpH> 10% during volume loading was 36–52%. While dAVVpH was found to be increased in non‐survivors (n= 27) when compared to survivors (0.32 ± 0.01 vs. 0.24±0.1, P<0.05) at the second day in the IUC, dVVApCO2 was not a significant predictor of mortality despite the fact that CI was found to be decreased in the non‐survivors (3.5 ±0.94 vs. 4.3±1.0 L min‐1 m‐2, P<0.01). In conclusion, the veno‐arterial carbon dioxide gradient was found to be inversely correlated to cardiac performance in patients both in patients with septic shock and in non‐septic post‐operative patients. The arterio‐venous gradient for pH was increased in low flow states, but this association was weaker. However of these two indices evaluated, only a raised dAVVpH was a significant predictor of later mortality.