bluuebunny/crossref_metadata_2025 huggingface dataset:
Polymorphonuclear leucocyte dysregulation in patients with gram‐negative septicaemia assessed by flow cytometry
Authors: WENISCH C. , PARSCHALK P. , HASENHÜNDL M. , GRIESMACHER A. , GRANINGER W.
Published: March 2008

Abstract. Flow cytometry was used to study phagocytic function and release of reactive oxygen intermediates (ROI) following phagocytosis by granulocytes in 14 patients (six female, eight male) with gram‐negative septicaemia prior to, during, and after therapy compared with a group of healthy controls. Phagocytic capacity was assessed by measuring uptake of fluorescein isothiocyanate (FITC)‐labelled bacteria. Reactive oxygen generation after phagocytosis was measured by the quantification of dihydrorhodamine 123 converted to rhodamine 123 intracellulary. Compared with results in healthy controls granulocytes of septicaemic patients exhibited a decreased capacity to phagocytize Escherichia coli and to generate reactive oxygen products. Both phagocytosis and ROI production increased after initiation of therapy and normalized within 7 days of treatment. The results suggest that granulocytes do not only participate in, but are also a target of, the septic host inflammatory response.
Urinary excretion of epidermal growth factor in living human kidney donors and their recipients
Authors: JØRGENSEN P. E. , KAMPER A.‐L. , MUNCK O. , STRANDGAARD S. , NEXØ E.
Published: March 2008

Abstract. Epidermal growth factor (EGF) is a growth‐promoting peptide that is synthesized in the distal tubules of the kidney and excreted in urine. EGF has been suggested to play a role in the repair after renal tissue damage, as well as in compensatory growth of the remaining kidney after uninephrectomy. The present study examined the urinary EGF excretion after uninephrectomy and transplantation among relatives. The urinary EGF excretion rate and the glomerular filtration rate (GFR) were followed for 26–54 days in 16 healthy kidney donors and nine recipients. After uninephrectomy the median urinary EGF excretion rate in the donors was not 50% of the pre‐operative value, but around 65% (95% confidence limits of the median on the fifth post‐operative day: 59–72%). This suggests that there is a compensatory increase in the EGF excretion rate from the remaining kidney of around 30% after uninephrectomy. A similar compensatory increase was demonstrated for GFR, indicating that the compensatory changes in EGF excretion rate and GFR might be correlated. In the transplanted kidneys, GFR was consistently around 15% lower and EGF excretion rate around 40% lower than in the corresponding kidneys remaining in the donors. This might reflect ischaemic and drug‐induced damage of the transplanted kidneys. The present study demonstrated a compensatory increase of around 30% in urinary EGF excretion from the remaining kidney after uninephrectomy in healthy humans. Whether EGF plays a role in the adaptive processes in the remaining kidney or whether changes in EGF excretion are merely of a secondary nature is still uncertain.
Relationship of apolipoproteins Al, B and lipoprotein Lp(a) to hepatic function of liver recipients during the early post‐transplant period
Authors: ARMSTRONG V. W. , SCHÜTZ E. , KALTEFLEITER M. , LUY M. , HELMHOLD M. , WIELAND E. , RINGE B. , OELLERICH M.
Published: March 2008

Abstract. To evaluate serum apo AI, apo B, Lp(a) and the ratio of unesterified cholesterol to total cholesterol as markers of hepatic synthetic capacity after orthotopic liver transplantation, serial measurements of these variables were performed on post‐transplant days 1, 3, 5, 7, 10 and 14 in 70 patients. Liver function was assessed by a quantitative dynamic test based on the hepatic conversion of lidocaine to monoethylglycinexylidide (MEGX). Patients were divided into two groups on the basis of clinical and laboratory findings, those with evidence (n= 46) and those without evidence (n= 24) of hepatic dysfunction. Apo AI levels fell in both groups to day 5, but then began to increase in the group with good hepatic function, a highly significant (P& 0001) positive correlation being found with the results of the MEGX test on post‐transplant days 7, 10 and 14. The ratio of unesterified cholesterol to total cholesterol rose in both groups from days 1 to 7 and then began to fall in the group without hepatic dysfunction; a highly significant (P< 0.001) negative correlation was observed with the results of the MEGX test on days 10 and 14. Apo B levels rose in both groups from days 1 to 10, with no significant differences between the two groups; no correlation was observed with the results of the MEGX test on any study day. In contrast, serum Lp(a) concentrations fell in both groups to day 5, but then began to increase in patients with good hepatic function; a highly significant (P<0001) positive correlation with the results of the MEGX test was recorded on post‐transplant day 14. We conclude that serial measurements of serum apo AI, Lp(a) and the ratio of unesterified cholesterol to total cholesterol are of value in monitoring the restoration of hepatic synthetic capacity in patients after orthotopic liver transplantation.
The influence of ulnar nerve blockade on skin microvascular blood flow*
Authors: NETTEN P. M. , WOLLERSHEIM H. , GIELEN M. J. M. , AREND J. A. C. J. DEN , LUTTERMAN J. A. , THIEN Th.
Published: March 2008

Abstract. Microvascular research is seriously hampered by the great temporal and spatial variability of the measured skin blood flow and variation in sympathetic vasomotor reflexes within and between persons. Therefore skin vasomotor reflexes were studied before and after ulnar nerve blockade within the same person, resulting in a temporal complete denervation of the fifth finger and partial denervation of the fourth finger. Skin temperature and laser Doppler flux (LDF) were registrated to measure predominantly arteriove‐nous shuntflow. Measurements were performed on the palmar tip of the second and fifth finger in nine healthy volunteers, at baseline, and during a sympathetic reflex test (i.e. inspiratory gasp) and postural response test. Beat‐to‐beat digital blood pressure was recorded from the third and fourth finger by a Finapres device. Baseline capillary blood cell velocity (CBV) was measured at the nailfold of the second and the fifth finger. After ulnar blockade baseline skin temperature, LDF and CBV increased significantly, with respectively (mean±SE) 3.2±0.9d̀C, 20.9 ±5.9 relative perfusion units and 0.79 ±0.40 mm‐1 s. The percentage LDF decrease of the fifth finger during inspiratory gasp was 48.2 ±5.3% before and 31 ±0.9% after blockade. The postural response test showed a decrease in LDF of the fifth finger with no significant difference before and after blockade, respectively 12.3± 14.7% and 8.0±2.7%, while no difference was found in the increase in digital blood pressure in the denervated fourth finger compared to both the same finger before blockade and to the third non‐blocked finger. It is concluded that ulnar nerve blockade enables the study of sympathetic skin vasomotor reflexes by comparison of a denervated and a non‐denervated vascular bed within the same person. After ulnar blockade arteriovenous shunt flow as well as nutritional capillary blood flow increased significantly. Postural vasoconstrictor response is not abolished by ulnar blockade, suggesting that local regulatory mechanisms are more important.
Albumin affects erythrocyte aggregation and sedimentation
Authors: REINHART W. H. , NAGY C.
Published: March 2008

Abstract. Erythrocyte aggregation and sedimentation is determined by the concentration of high molecular plasma proteins such as fibrinogen and immuno‐globulins. The role of albumin, the most abundant plasma protein, is controversial. We analysed the influence of human albumin (0–80 gL‐1) on sedimentation behaviour of erythrocytes suspended (haematocrit 35%) in fibrinogen‐enriched normal plasma, plasma from patients with hypoalbuminae‐mia, solutions of dextran 70 in buffer, and mixtures of fibrinogen, immunoglobulins and albumin in buffer. Sedimentation was measured by the Westergren method, viscometry was performed at low and high shear rate. The addition of albumin to normal plasma, hypoalbuminaemic plasma, or dextran solutions in buffer decreased the erythrocyte sedimentation rate. In contrast, in a mixture of fibrinogen and immunoglobulins in buffer, albumin increased erythrocyte sedimentation. When either fibrinogen or immunoglobulins were omitted, or fibrinogen was replaced by dextran, albumin did not increase sedimentation, which indicates that increased sedimentation was due to an interaction of all three compounds. The viscosity of erythrocyte suspensions was increased by albumin. It is concluded that the influence of albumin on erythrocyte aggregation is complex and depends on the technique used; low shear viscosity is increased, but erythrocyte sedimentation, i.e. under no flow conditions, is decreased. The inhibitory action of albumin on the erythrocyte sedimentation rate has clinical implications and must be known by physicians. It may help to interpret sedimentation rates more correctly and prevent misinterpreting presumed therapeutic successes or failures.
Left ventricular hypertrophy is associated with a stronger impairment of non‐oxidative glucose metabolism in hypertensive patients
Authors: PAOLISSO G. , GALZERANO D. , GAMBARDELLA A. , VARRICCHIO G. , SACCOMANNO F. , D'AMORE A. , VARRICCHIO M. , D'ONOFRIO F.
Published: March 2008

Abstract. Hypertensive patients with left ventricular hypertrophy (LVH) have a higher degree of hyper‐insulinaemia than hypertensive patients without LVH. Obese patients with LVH have also been demonstrated to have a very low glucose disappearance rate after an intravenous glucose bolus. No studies have investigated the difference in insulin action and substrate oxidation in hypertensive patients with and without LVH. For this reason 36 subjects were enrolled for our study: (1) healthy control subjects (n=10); (2) hypertensive patients without LVH (n= 12); and (3) hypertensive patients with LVH (n= 14). All subjects underwent an oral glucose tolerance test (OGTT, 75 g of glucose) and a euglycaemic hyperinsulinaemic glucose clamp (insulin infusion rate, 71 pmol(kgmin)‐1 for 120min). In this latter test indirect calorimetry allowed substrate oxidation determination. Echocardiographic methods allowed LVH assessment. Hypertensive patients with LVH had the lowest insulin‐mediated nonoxidative glucose metabolism compared to hypertensive patients without LVH (P<0.01) and to healthy subjects (P< 0.001). In the whole group of hypertensive patients (n= 26), partial correlations showed left ventricular mass index (LVMI) associated with fasting plasma insulin levels (r= 0.44 P<0.005), insulin‐mediated whole body glucose disposal (r= ‐0.41 P<0.01) and nonoxidative glucose metabolism (r= ‐0.33 P<0.04) independently of age, body weight, systolic blood pressure and plasma catechola‐mines levels. In conclusion, our data provide evidence that LVH in hypertensive patients is associated with a worsening in nonoxidative glucose metabolism.
Elevation of D‐glucose impairs coronary artery autoregulation after slight reduction of coronary flow
Authors: WASCHER T. C. , BACHERNEGG M. , KICKENWEIZ E. , STARK G. , STARK U. , TOPLAK H. , GRAIER W. F. , KREJS G. J.
Published: March 2008

Abstract. Diabetes mellitus is thought to increase the susceptibility of tissue to hypoxic injury through d‐glucose‐induced alterations of intracellular. metabolism. Therefore the effects of hyperglycaemia on coronary artery autoregulation under slight reduction of coronary flow were investigated in isolated perfused guinea‐pig hearts. Under normal (10 mM) d‐glucose concentrations coronary autoregulation was intact in response to a slight reduction of coronary flow (from 6 to 4.5 mL min‐1) when L‐arginine as a precursor of the endothelium‐derived relaxing factor (EDRF/NO) was available and formation of prosta‐glandines was intact. Under high (44 mM) D‐glucose concentrations on the other hand, a sustained vasodi‐latation dependent on the availability of L‐arginine was observed, when formation of prostaglandins was blocked. This effect was partially reduced in the presence of prostaglandin synthesis. Furthermore, the effect of L‐arginine under both conditions could be antagonized by the L‐arginine‐analogue NAG‐nitro‐L‐arginine‐methyl‐ester (100 μm). Our results suggest that hyperglycaemia impairs coronary artery autoregulation by reducing the threshold for hypoxic vasodilatation in an EDRF/NO‐dependent manner. Concomitantly a shift from the formation of vaso‐dilatatory to vasoconstrictive prostaglandines was observed. These results might be of particular interest in patients with diabetes mellitus and ischaemic heart disease.
Treatment of systemic mastocytosis with interferon‐γ: failure after appearance of anti‐IFN‐γ antibodies
Authors: FIEHN C. , PRÜMMER O. , GALLATI H. , HEILIG B. , HUNSTEIN W.
Published: March 2008

Abstract. We report a case of a patient with systemic mastocytosis who was treated with interferon‐γ. Because of severe diarrhoea, nausea and weight loss due to mast cell infiltration of the gastric mucosa the patient received 150μg d‐1 interferon‐γ subcutan‐eously for 10 months. During therapy, the plasma concentrations of IL‐3, IL‐4 and GM‐CSF, which seem to play a role in mast cell growth and differentiation were monitored. The patient had good symptomatic relief and the initially very high eosinophil counts in the pripheral blood showed a partial reduction. However, after 4 months of therapy the patient relapsed. In serum obtained after the relapse, but not in stored serum from the beginning of the therapy, neutralizing antibodies against interferon‐γ were found. Therefore an initial response to the therapy and a secondary failure mediated by treatment‐induced antibodies against recombinant interferon‐γ might be suggested. Interferon‐γ may be a well tolerated therapeutic option in systemic mastocytosis. However, treatment‐induced neutralizing antibodies against recombinant interferon‐γ should be considered if secondary treatment failure occurs.
Effects of cholestyramine on gallbladder and gastric emptying in obese and lean subjects
Authors: PORTINCASA P. , CIAULA A. DI , PALMIERI V. , BERGE‐HENEGOUWEN G. P. VAN , PALASCIANO G.
Published: March 2008

Abstract. Gallbladder stasis is frequent in obese subjects and may contribute to their increased risk for gallstone formation. The bile salt sequestrant cholestyramine acutely enhances postprandial gallbladder emptying in lean subjects, through dis‐inhibition of a negative feedback between intraluminal bile salts and CCK release. In this study the effect of cholestyramine on both gallbladder and gastric antrum dynamics were studied by realtime ultrasonography in 12 obese and 15 lean subjects. For the acute study, on different days, subjects ingested a liquid meal (two egg yolks plus water 200 mL, 50 kJ) or a meal with 4g cholestyramine. Gallbladder emptying was impaired in obese patients who had significantly larger fasting gallbladder volume (39.4 ± 6.9 vs. 21.6 ± l.7mL, P<0.02), larger residual volume (12.3 ± 1.8 vs. 4.0 ± 0.5ml, P< 0.0006) and slower emptying time (T/2: 33 ± 2 vs. 21 ± 2 min, P < 0.05) than lean subjects. Integrated antral emptying was also less in obese than lean subjects (5521 ± 578 vs. 7908 ± 491 % 120min‐1, P<0.02). Cholestyramine enhanced postprandial gallbladder emptying in both obese and lean subjects. Gastric emptying was delayed with cholestyramine in lean but not obese subjects. For the chronic study, after 1 month therapy with cholestyramine (4 g every 2 days), the motility tests were repeated in nine obese subjects. Gallbladder and gastric responses to a test meal, with or without cholestyramine, were preserved. We conclude that both gallbladder and antral emptying of a liquid test meal are impaired in obese subjects. Gallbladder emptying improves after acute administration of a low dose cholestyramine with test meal. This effect is sustained after 1 month treatment with a low dose of cholestyramine and does not interfere with gastric emptying of obese patients. Cholestyramine may improve gallbladder hypomotility in obese people.
The effect of recombinant human IGF‐I on protein metabolism in post‐operative patients without nutrition compared to effects in experimental animals
Authors: SANDSTRÖM R. , SVANBERG E. , HYLTANDER A. , HAGLIND E. , OHLSSON C. , ZACHRISSON H. , BERGLUND B. , LINDHOLM E. , BREVINGE H. , LUNDHOLM K.
Published: March 2008

Abstract. This study has evaluated the effects of recombinant human insulin‐like growth factor I (rhIGF‐I) to moderately stressed post‐operative patients provided with dextrose as the only exo‐geneous substrate. Thirty patients who underwent elective colorectal surgery were randomized to receive either rhIGF‐I (80μg kg‐1 bw) subcutaneously twice daily or placebo injections in a double‐blind parallel group design. Nitrogen balance, urinary 3‐methyl‐histidine excretion plasma growth hormone (GH), serum cortisol, IGF‐I binding proteins (IGFBP‐1,3), glomerular filtration rate, plasma amino acid concentrations and whole‐body energy expenditures were measured as effector variables during days 1–5 post‐operatively. Animal and isolated tissue experiments were performed as additional control experiments to confirm cellular effectiveness of the recombinant material. rhIGF‐I increased significantly the glomerular filtration rate and prevented the adaptive decrease in whole‐body energy expenditure in response to partial starvation in the postoperative period. Serum and plasma concentrations of IGFBP‐1,3 cortisol, blood glucose and amino acids were not significantly influenced by rhIGF‐I administration, while plasma GH levels decreased significantly as expected. rhIGF‐I had no effect on either nitrogen balance or protein breakdown (3‐methylhistidine excretion) in post‐operative patients on dextrose supplementation only, although plasma concentrations of IGF‐I increased from 130 140 ngmL‐1 to a range of 300–450 ngmL‐1. In contrast, IGF‐I stimulated the synthesis of both globular and myofibrillar proteins (+50%, P<0.01), when given as a single dose (100μgkg‐1) 2 h before measurements of protein synthesis in skeletal muscles of overnight fasted adult mice. This stimulatory effect by IGF‐I (1μgmL‐1) was also confirmed by measurements of skeletal muscle protein synthesis in vitro (+40%, P<0.05). Orally re‐fed mice had a normal transcription of IGF‐I mRNA in skeletal muscle cells, while overnight fasted mice showed a trend to down‐regulated transcription. Our results demonstrate that rhIGF‐I has several significant physiological effects, without major side‐effects, when supplied to partially starved patients in the post‐operative phase. The lack of a whole‐body nitrogen sparing effect by rhIGF‐I alone to postoperative patients is not clear, but was most likely explained by subnormal plasma concentrations of amino acids.
A comparison of the effects of insulin‐like growth factor‐I, insulin and combined infusions of insulin and insulin‐like growth factor4 on glucose metabolism in dogs
Authors: SHOJAEE‐MORADIE F. , UMPLEBY A. M. , THOMASON M. J. , JACKSON N. C. , BOROUJERDI M. A. , SÖNKSEN P. H. , SKOTTNER A. , JONES R. H.
Published: March 2008

Abstract. The effect of infusions of recombinant insulin‐like growth factor‐I (IGF‐I) (34, 103 or 688pmol kg‐1min‐1), insulin (3.4, 10.3 or 68.8pmol kg‐1min‐1) or combined infusions (34pmol IGF‐I+ 3–4pmol kg‐1 min‐1 insulin or 103pmol IGF‐I + 3–4pmolkg‐1 min‐1 insulin) on glucose metabolism was investigated in dogs using a [3‐3H]‐glucose infusion and euglycaemic clamp. All insulin doses decreased glucose production rate (Ra) in a dose‐dependent manner (P<0.05). All IGF‐I doses decreased glucose Ra (P < 0.05) but this decrease was not dose dependent. The decrease in glucose Ra with the combined infusion of 34pmolkg‐1min‐1 IGF‐I + 3–4pmolkg‐1min‐1 insulin was greater than 34 pmol kg‐1 min‐1 IGF‐I (P < 0.05) but not different from 3.4 pmol kg‐1 min‐1 insulin. All insulin and IGF‐I doses increased glucose utilization rate (Rd) in a dose‐dependent manner (P < 0.01). The increase in glucose utilization was greater following both combined infusions than with either component infused alone (P < 0.05). Although at the doses selected, insulin and IGF‐I had similar effects on glucose utilization with additive effects when the two peptides were combined, IGF‐I was less effective than insulin in suppressing glucose production.
Interactions between platelets and neutrophils in essential thrombocythaemia. Effects on neutrophil chemiluminescence and superoxide anion generation
Authors: CARULLI G. , MINNUCCI S. , GIANFALDONI M. L. , ANGIOLINI C. , AZZARÄ A. , AMBROGI F.
Published: March 2008

Abstract. Essential thrombocythaemia (ET) is frequently associated with neutrophil and platelet dysfunction, and with increased incidence of vascular complications (thrombosis, haemorrhage). Several interactions between platelets and neutrophils have been reported, and the reciprocal actions between these cells may have an important role both in thromboregulation and in diseases such as those caused by uncontrolled neutrophil activation. In the current paper the authors studied 15 patients affected by ET and 10 normal subjects as controls. Circulating neutrophils and platelets were purified and were re‐combined in constant ratios (50:1, 100:1 and 200:1) and the individual platelet to neutrophil ratio. Super‐oxide anion (O‐2) generation and luminol‐enhanced chemiluminescence (CL) were studied after neutrophil stimulation with fMLP. In normal subjects both O‐2 generation and CL were inhibited by autologous platelets in a dose‐dependent manner. In ET patients, on the contrary, platelet‐dependent inhibition of O‐2 generation did not occur, while a dose‐dependent inhibition of CL was observed. Two groups of ET patients were found: patients with neutrophil O‐2 generation and CL within the normal range, and patients with significantly reduced neutrophil respiratory burst. However, no differences were found between these two groups of patients in terms of platelet effects towards fMLP‐stimulated neutrophils. Therefore, platelets from ET patients were not able to exert the homeostatic control towards neutrophil O‐2 generation shown by platelets from normal subjects, and this phenomenon may have a role in the clinical setting. In fact, O‐2 has been shown to be a very strong direct platelet activator, is able to inactivate nitric oxide (which is a powerful inhibitor of platelet aggregation and adhesion to endothelium), and is directly involved in neutrophil‐mediated tissue damage.
Detection improvement of cytomegalovirus antigen in human peripheral blood using monoclonal antibodies and automated reading of cell preparations
Authors: BOLAND G. J. , MESKER W. E. , DOORN R. , PLOEM‐ZAAIJER J. J. , TANK H. J. , GAST G. C. DE
Published: March 2008

Abstract. One of the major drawbacks in cytomegalovirus (CMV)‐antigenaemia detection for diagnosis of active CMV infection is the low number of CMV‐antigen positive cells present in peripheral blood. It is therefore necessary to screen large numbers of peripheral blood granulocytes to find only a few antigen‐positive cells. We have optimized this detection by testing several monoclonal antibodies (mAb) to CMV‐antigens (mAbs C10/C11, C12, BM222, E13 and SL20). In total 550 blood samples from 40 patients were investigated. More blood samples were found positive with mAb C12 than with the other mAbs. Also the average number of positive cells per slide was highest for mAb C12. Furthermore, duplicate slides were examined automatically using an image analysis system (LEYTAS) and compared to visual detection (cytospin slides). The detection sensitivity of both screening methods was compared for mAb C12. In total 360 slides were analysed, from positive as well as negative blood samples. The sensitivity of the automated screening was 93% and for the visual evaluation of the cytospin slides 73%. In conclusion, mAb C12 was the most suitable of the mAbs tested for detection of antigenaemia, and automatic detection of CMV antigenaemia with image analysis of slides is a sensitive method due to the large numbers of cells that can be screened.
Lipoprotein (a) in patients with hyperlipidaemia
Authors: BARTENS W. , RADER D. J. , TALLEY G. , JR H. B. BREWER
Published: March 2008

Abstract. Lipoprotein (a) [Lp(a)] is an atherogenic lipoprotein which is similar in structure to, but meta‐bolically distinct from, LDL. Factors modulating plasma Lp(a) concentrations are poorly understood. We hypothesized that patients with hyperlipidaemia have elevated Lp(a) levels and determined the pheno‐type, concentration and distribution of Lp(a) in a group of hyperlipidaemic patients (n=107) compared with a control group (n= 128). Lp(a) concentrations were significantly increased in the hyperlipidaemic patients (mean, 34pM4mgdL‐1; median, 19mgdL‐1) as compared with the controls (20pM3mgdL‐1; 9mgdL‐') (P<0.01). Interestingly, after dividing the patients into one group with elevated cholesterol (>200mgdL‐1) (n = 44) and another group with elevated triglycerides (>200mgdL‐1) (n = 51) we found that Lp(a) concentrations were 2.3‐fold higher in the high cholesterol patients (mean, 45 pM 5; median, 41mgdL‐1) compared to the high triglyceride subjects (20pM 4; 8mgdL‐1) (P<0.01). Furthermore, a negative correlation between triglyceride and Lp(a) plasma concentrations was found in patients exhibiting triglyceride levels > 300mgdL‐1 (r=‐0–41, P = 004, n = 36) and with triglycerides >400mgdL‐1 (r=‐0–52, P = 003, n=17). These data indicate that plasma Lp(a) concentrations are elevated in hyperlipidaemia if the patients have high cholesterol levels, whereas Lp(a) is normal to low in patients with elevated triglycerides. The dominating lipid elevation in this condition and increased Lp(a) levels may contribute to the increased risk of premature coronary artery disease (CAD) in hyperlipidaemic patients.
Effect of polymorphism in the insulin gene region on IDDM susceptibility and insulin secretion**
Authors: HALMINEN M. , VEIJOLA R. , REIJONEN H. , ILONEN J. , ÅKERBLOM H. K. , KNIP M.
Published: March 2008

Abstract. In addition to the major genetic determinants of insulin‐dependent diabetes mellitus (IDDM) in the major histocompatibility complex (MHC) on chromosome 6, there are also minor genetic risk markers, e.g. in the insulin gene region on chromosome 11p15.5 (IDDM2). We studied the significance of the ‐23 HphI polymorphism in the insulin gene region (‐23 HphI INS) in the Finnish population in combination with HLA genotyping data. The frequency of the ‐23 HphI INS +/+ genotype was higher in diabetic subjects with a low risk HLA DQBI genotype than in control subjects (P= 0.05). Diabetic children in multiple‐case families also had a higher frequency of the INS risk genotype than the controls (P<0.05), and this difference was independent of the HLA genotype. Furthermore, we studied siblings positive for islet cell antibodies (ICAs) and/or insulin autoantibodies (IAAs) to evaluate the impact of the ‐23 HphI INS +/+ genotype on their beta‐cell function assessed by sequential intravenous glucose tolerance tests and on their progression to IDDM. When analysing siblings with a low‐risk HLA DQBI genotype, those with the ‐23 HphI INS +/+ genotype had lower first phase insulin responses (P <0.02) on several occasions than the remaining sibling. Six siblings (26.1%) in the former group progressed to clinical disease during the observation period, whereas none in the latter group presented with IDDM (P= 0.01). These observations suggest that the ‐23 HphI INS +/+ polymorphism is associated with an increased risk of IDDM in subjects without predisposing genes in the MHC region. The enhanced susceptibility may be related to a reduced insulin secretory capacity.
Hyperhomocysteinaemia—a common finding in a psychogeriatric population
Authors: NILSSON K. , GUSTAFSON L. , FÄLDT R. , ANDERSSON A. , BRATTSTRÖM L. , LINDGREN A. , ISRAELSSON B. , HULTBERG B.
Published: March 2008

Abstract. Plasma homocysteine concentration is a sensitive marker for cobalamin and folate deficiency. The previously reported high incidence of increased plasma homocysteine in psychogeriatric patients and the association between reduced concentrations of cobalamin, folate and neuropsychiatric symptoms led to the present study on 741 consecutive psychogeriatric patients. The concentrations of plasma homocysteine correlated significantly with blood folate, serum cobalamin and serum creatinine both in demented (n= 295) and in non‐demented patients with other psychiatric disorders (n= 215). Plasma homocysteine concentrations were significantly increased in both the demented and the non‐demented patients, whereas only the demented patients had lower blood folate and serum creatinine concentrations than 163 control subjects. Almost all of the different diagnostic groups of demented and non‐demented patients exhibited significantly increased plasma homocysteine concentrations compared with control subjects. Significantly decreased blood folate concentrations were mainly found in the different diagnosis groups of demented patients. Plasma homocysteine concentrations in both demented and non‐demented patients with serum cobalamin and blood folate above the lower 20th percentile of these vitamins in the control subjects were also studied. Despite these vitamin concentrations, both groups of patients still exhibited significantly higher plasma homocysteine concentrations than the control subjects, which may indicate an increased frequency of impaired genetic capacity to metabolize homocysteine in these patients. Patients with either dementia of vascular cause or a history of other occlusive arterial disease had a significantly higher plasma homocysteine concentration than those without a history of vascular disease.
Lack of effect of desmopressin on ACTH and cortisol responses to ovine corticotropin‐releasing hormone in anorexia nervosa
Authors: FOPPIANI L. , SESSAREGO P. , VALENTI S. , FALIVENE M. R. , CUTTIC C. M. , DISEM M. GIUSTI
Published: March 2008

Abstract. Both arginine vasopressin (AVP) and corticotropin‐releasing hormone (CRH) are involved in the release of ACTH in man. Desmopressin (DDAVP), a synthetic analogue of AVP, has been shown to have a CRH‐like action (able to promote ACTH and cortisol release) in animals but not in normal man. Nevertheless, DDAVP is able to release ACTH and cortisol in ACTH‐dependent Cushing's disease. We studied eight anorexia nervosa (AN) patients [as AN is a condition in which chronic activation of the hypothalamic‐pituitary‐adrenal (HPA) axis is commonly reported] in a refeeding phase of the disease, to evaluate whether, after weight gain, ACTH and cortisol response to ovine corticotropin‐releasing hormone (oCRH) [1 μg kg‐1 body weight (BW) i.v.] is restored. We also wanted to ascertain the effect on the HPA axis of 10 μg i.v. DDAVP alone and as pretreatment to oCRH (1 μg kg‐1 BW i.v.)‐induced secretion of ACTH and cortisol. We studied six normal women as control subjects. No significant differences in ACTH and cortisol responses to oCRH were found between AN patients and control subjects. DDAVP was not able to stimulate ACTH or cortisol release in AN patients or in control subjects, but in the latter it was able to significantly enhance (P < 0.05) ACTH [area under curve (AUC): 590.0± 104.4 pmol L‐1 120 min‐1 and cortisol (AUC: 28899.0 ± 6935.2nmol L‐1 120 min‐1) responses to oCRH (ACTH AUC: 325.7 ± 101.7 pmol L‐1 120 min‐1, cortisol AUC: 14197.4 ± 2930.0 nmol L‐1 120 min‐1). The present data show that DDAVP does not stimulate ACTH and cortisol in AN patients or, as previously reported, in normal subjects. However, DDAVP is able to enhance ACTH and cortisol release after oCRH administration in normal subjects but not in AN patients. This finding could be due to a down‐regulation of hypophyseal DDAVP V3 receptors in AN as a direct consequence of the hypercortisolaemic status usually present.
Defective biliary copper excretion in Wilson's disease: the role of caeruloplasmin
Authors: DAVIS W. , CHOWRIMOOTOO G. F. E. , SEYMOUR CAROL A.
Published: March 2008

Abstract. Previous studies have failed to explain the link between copper accumulation and abnormal caeruloplasmin expression in Wilson's disease. Furthermore, despite the isolation of a candidate gene for Wilson's disease, which predicts a defective copper transport protein, the localization of this putative protein and its relationship to the pathway involved in copper excretion and to caeruloplasmin remain unknown. We now present evidence that caeruloplasmin, the major plasma copper‐carrying protein, is present in the liver in Wilson's disease, and thus that reduced circulating levels of the protein result from a post‐translational defect in the secretory pathway. We have also identified a novel form of caeruloplasmin, molecular weight 125 kD, which we propose may act as the carrier for excretory copper into bile, since it is normally present in both liver and bile, although largely absent from serum, and undetectable in bile from Wilson's disease patients. The presence of this form of caeruloplasmin in Wilson's disease liver suggests that a related post‐translational defect may also be responsible for its absence from bile in Wilson's disease. This study thus provides the first plausible explanation of a link between the defective copper excretion and the reduced plasma caeruloplasmin, which characterize Wilson's disease.
The value of serial determination of MEGX and hyaluronic acid early after orthotopic liver transplantation
Authors: SCHÜTZ E. , LUY‐KALTEFLEITER M. , KALTEFLEITER M. , BURDELSKI M. , RINGE B. , ARMSTRONG V. W. , OELLERICH M.
Published: March 2008

Abstract. Post‐transplant assessment of early graft function has become an essential part of monitoring, especially when deciding on retransplantation. If primary non‐function is indicated, retransplantation is inevitable; early graft dysfunction may be related to subsequent complications. In a prospective study in 84 patients after orthotopic liver transplantation (OLT) we measured aspartate aminotransferase (AST), alanine aminotransferase (ALT), glutamate dehydrogenase (GLDH), bilirubin (BIL), prothrombin time, MEGX formation, hyaluronic acid (HA) and soluble interleukin‐2 receptor (sIL‐2R) concentrations during the first 2 postoperative weeks; graft outcome was followed over 4 months. The aim of this study was to determine whether graft survival could be predicted by such variables early after OLT. Compared with patients with stable graft function (n= 25), patients with post‐transplant icteric cholestasis (n= 30) exhibited no difference in graft survival, despite a decrease in MEGX formation to a nadir median of 12 μgL‐1 on day 10. Patients with rejection (n= 8) and septicaemia (n= 6) showed a marked decrease in MEGX values and an increase in HA and sIL‐2R concentrations between postoperative days 3 and 7. Patients with primary non‐function (PNF; n= 5) were characterized by strongly reduced MEGX formation (median 4 μgL) and increased HA values (median 2300 μgL‐1) on day 3 after OLT. A total of 24/84 grafts were lost within 120 days. In a survival analysis using the Cox proportional hazards regression, HA and MEGX values on day 1 were the only independent variables entering the model that showed an adequate prognostic sensitivity. At cut‐off points of 22 μgL‐1 (MEGX) and 730 μgL‐1 (HA) the combined use of these parameters in a parallel approach yielded a sensitivity of 58% with a corresponding specificity of 95% for 120‐day graft survival. These findings suggest that the inclusion of MEGX and HA in postoperative monitoring of OLT patients may be helpful in the early prediction of graft survival.
Effect of hypercholesterolaemia on platelet growth factors
Authors: GARCIA‐BOLAO I. , MERINO J. , MARTÍNEZ A. , GRAU A. , ALEGRÍA E. , MARTÍNEZ‐CARO D.
Published: March 2008

Abstract. Evidence from several sources suggests that important interactions occur between platelets and low‐density lipoproteins. This study was undertaken to find out if diet‐induced hypercholesterolaemia affects the growth factor content in circulating platelets. Minipigs were fed either normal diet supplemented with 2% cholesterol (n= 12) or normal diet alone (n= 12). After 4 months, mean platelet volume was significantly lower (P < 0.05) and monocyte count was significantly higher (P < 0.05) in the cholesterol group. Serum and intraplatelet levels of platelet‐derived growth factor (BB homodimer) and transforming growth factor beta 1 were statistically unchanged after diet. Hypercholesterolaemia did not affect the proliferative effect of either serum or platelet lysates on porcine vascular smooth muscle cells and Swiss‐3T3 cells in culture. A significant positive correlation between Swiss‐3T3 and smooth muscle cell proliferation was present in both groups. These results suggest that the atherosclerosis‐promoting effect of hypercholesterolaemia cannot be explained by its direct effect on smooth muscle cell proliferation or by changes in serum or intraplatelet concentrations of growth factors.
Lipoprotein lipase gene mutations D9N and N291S in four pedigrees with familial combined hyperlipidaemia
Authors: BRUIN T. W. A. DE , MAILLY F. , BARLINGEN H. H. J. J. VAN , FISHER R. , CABEZAS M. CASTRO , TALMUD P. , DALLINGA‐THIE G. M. , HUMPHRIES S. E.
Published: March 2008

Abstract. The role of the lipoprotein lipase (LPL) gene in familial combined hyperlipidaemia (FCH) is unclear at present. We screened a group of 28 probands with familial combined hyperlipidaemia and a group of 91 population controls for two LPL gene mutations. D9N and N291S. LPL‐D9N was found in two probands and one normolipidaemic population control. LPL‐N291S was found in four probands and four population controls. Subsequently, two pedigrees from probands with the D9N mutation and two pedigrees from probands with the N291S mutation were studied, representing a total of 24 subjects. Both LPL gene mutations were associated with a significant effect on plasma lipids and apolipoproteins. Presence of the D9N mutation (n = 7) was associated with hypertriglyceridaemia [2.69± 1.43 (SD) mmol L‐1] and reduced plasma high‐density lipoprotein cholesterol (HDL‐C) concentrations (0.92± 0.21 mmol L‐1) compared with 11 non‐carriers (triglyceride 1.75± 0.64 mmol L‐1; HDL‐C 1.23± 0.30 mmol L‐1, P= 0.03 and P= 0.025 respectively). LPL‐D9N carriers had higher diastolic blood pressures than non‐carriers. LPL‐N291S carriers (n= 6) showed significantly higher (26%) apo B plasma concentrations (174± 26 mg dL‐1) than non‐carriers (138± 26 mg dL‐1; P= 0.023), with normal post‐heparin plasma LPL activities. Linkage analysis revealed no significant relationship between the D9N or N291S LPL gene mutations and the FCH phenotype (hypertriglyceridaemia, hypercholesterolaemia or increased apo B concentrations). It is concluded that the LPL gene did not represent the major single gene causing familial combined hyperlipidaemia in the four pedigrees studied, but that the LPL‐D9N and LPL‐N291S mutations had significant additional effects on lipid and apolipoprotein phenotype.
Effects of the sulphydryl donor N‐acetyl‐L‐cysteine on nerve conduction, perfusion, maturation and regeneration following freeze damage in diabetic rats
Authors: LOVE A. , COTTER M. A. , CAMERON N. E.
Published: March 2008

Abstract. Peripheral nerve conduction velocity deficits in diabetic rats depend on decreased nerve perfusion, which may be related to increased free radical activity and impaired endogenous protection by the glutathione redox cycle. We studied the effect of treatment with the glutathione precursor N‐acetyl‐L‐cysteine on nerve conduction, blood flow, maturation and regeneration. Two months of diabetes in mature rats caused 20% and 48% deficits in sciatic motor conduction velocity and endoneurial blood flow, respectively, which were largely corrected by N‐acetyl‐L‐cysteine treatment during the second month. In young non‐diabetic rats, sciatic motor conduction velocity increased by 31% over 6 weeks. Diabetes halved the conduction velocity maturation rate, however N‐acetyl‐L‐cysteine treatment allowed a normal pattern of development. After 1 month of treated or untreated diabetes, the sciatic nerve was lesioned by a liquid nitrogen‐cooled probe. Myelinated fibre regeneration distance, determined electrophysiologically, was reduced by 12.2% with diabetes; this was prevented by N‐acetyl‐L‐cysteine treatment. Thus, the data stress the importance of free radical‐mediated changes in the aetiology of experimental diabetic neuropathy.
Involvement of the L‐arginine‐nitric oxide pathway in hyperglycaemia‐induced coronary artery dysfunction of isolated guinea pig hearts
Authors: WASCHER T. C. , BACHERNEGG M. , KICKENWEIZ A. , STARK G. , STARK U. , TOPLAK H. , GRAIER W. F.
Published: March 2008

Abstract. The effects of hyperglycaemia and L‐arginine on flow‐induced reduction of coronary artery resistance were investigated in isolated guinea pig hearts. In the presence of indomethacin, hyperglycaemia caused an increase in flow‐induced vasodilatation (P<0.05). Hyperosmotic controls failed to mimic this effect. Addition of L‐arginine strongly enhanced this effect. Addition of D‐arginine failed to mimic the effects of L‐arginine. The effect of L‐arginine was abolished by co‐administration of NG‐nitro‐L‐arginine. In the absence of indomethacin and L‐arginine, the effect of hyperglycaemia was blunted, suggesting the formation of vasoconstrictive prostanoids. Addition of L‐arginine again resulted in a significant increase in flow‐induced vasodilatation. In conclusion our results suggest that increased flow‐induced vasodilatation under hyperglycaemic conditions depends on an adequate supply of L‐arginine to maintain sufficient formation of nitric oxide.
Soil organic matter stabilization in acidic forest soils is preferential and soil type‐specific
Authors: Spielvogel S. , Prietzel J. , Kögel‐Knabner I.
Published: March 2008

Minerals with large specific surface areas promote the stabilization of soil organic matter (SOM). We analysed three acidic soils (dystric, skeletic Leptic Cambisol; dystric, laxic Leptic Cambisol; skeletic Leptic Entic Podzol) under Norway spruce (Picea abies) forest with different mineral compositions to determine the effects of soil type on carbon (C) stabilization in soil. The relationship between the amount and chemical composition of soil organic matter (SOM), clay content, oxalate‐extractable Fe and Al (Feo; Alo), and dithionite‐extractable Fe (Fed) before and after treatment with 10% hydrofluoric acid (HF) in topsoil and subsoil horizons was analysed. Radiocarbon age, 13C CPMAS NMR spectra, lignin phenol content and neutral sugar content in the soils before and after HF‐treatment were determined and compared for bulk soil samples and particle size separates. Changes in the chemical composition of SOM after HF‐treatment were small for the A‐horizons. In contrast, for B‐horizons, HF‐soluble (mineral‐associated) and HF‐resistant (non‐mineral‐associated) SOM showed systematic differences in functional C groups. The non‐mineral associated SOM in the B‐horizons was significantly depleted in microbially‐derived sugars, and the contribution of O/N‐alkyl C to total organic C was less after HF‐treatment. The radiocarbon age of the mineral‐associated SOM was younger than that of the HF‐resistant SOM in subsoil horizons with small amounts of oxalate‐extractable Al and Fe. However, in horizons with large amounts of oxalate‐extractable Al and Fe the HF‐soluble SOM was considerably older than the HF‐resistant SOM. In acid subsoils a specific fraction of the organic C pool (O/N‐alkyl C; microbially‐derived sugars) is preferentially stabilized by association with Fe and Al minerals. Stabilization of SOM with the mineral matrix in soils with large amounts of oxalate‐extractable Alo and Feo results in a particularly stable and relatively old C pool, which is potentially stable for thousands of years.
Amphibians as metrics of critical biological thresholds in forested headwater streams of the Pacific Northwest, U.S.A.
Authors: WELSH JR HARTWELL H. , HODGSON GARTH R.
Published: March 2008

1. Amphibians are recognized both for their sensitivity to environmental perturbations and for their usefulness as cost‐effective biometrics of ecosystem integrity (=system health).

2. Twenty‐three years of research in headwater streams in the Klamath‐Siskiyou and North Coast Bioregions of the Pacific Northwest, U.S.A., showed distinct patterns in the distribution of amphibians to variations in water temperature, % fine sediments and the amount of large woody debris (LWD).

3. Here, we review seven studies that demonstrate connections between species presence and abundance and these three in‐stream variables. These data were then used to calculate realized niches for three species, the southern torrent salamander, the larval coastal tailed frog and the larval coastal giant salamander, relative to two of these environmental stressors (water temperature and % fine sediments). Moreover, multivariate generalized additive models were used to predict the presence of these three amphibians when these three stressors act in concert.

4. Stream‐dwelling amphibians are shown to be extremely sensitive to changes in water temperature, amounts of fine sediment and LWD, and specific thresholds and ranges for a spectrum of animal responses can be used to manage for headwater tributary ecosystem integrity.

5. Consequently, amphibians can provide a direct metric of stream ecosystem integrity acting as surrogates for the ability of a stream network to support other stream‐associated biota, such as salmonids, and their related ecological services.
Plesiosaurs
Authors: Smith Adam Stuart
Published: March 2008

Plesiosaurs are an unusual and intriguing group of extinct aquatic reptiles (Fig. 1). They are sauropterygians, a group known from an array of semi‐aquatic forms during the Triassic period: placodonts, pachypleurosaurs and nothosaurs. The first plesiosaurs are known from the very latest Triassic, but by the Early Jurassic plesiosaurs were cosmopolitan in distribution and lasted successfully to the latest Cretaceous, when they became victims of the K‐T extinction event. Plesiosaurs were predominantly marine organisms, although their fossils are not uncommon in brackish or even fresh water deposits. We know that all plesiosaurs were carnivorous; many of them were top predators in their respective ecosystems. But with no living descendants (or analogues) plesiosaurs are mysterious fossil organisms—as we will see, many questions regarding their biology remain unanswered or contentious. However, plesiosaurs are currently undergoing renewed scientific attention.

The beautifully preserved skeleton of the plesiosaur Rhomaleosaurus victor seen in ventral view, from the Lower Jurassic (Toarcian) of Holzmaden, Germany (total length 3.44 m). Redrawn from Fraas (1910).

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