Isolation and sequence of complementary DNA encoding human extracellular superoxide dismutase.

A complementary DNA (cDNA) clone from a human placenta cDNA library encoding extracellular superoxide dismutase (EC-SOD; superoxide:superoxide oxidoreductase, EC 1.15.1.1) has been isolated and the nucleotide sequence determined. The cDNA has a very high G+C content. EC-SOD is synthesized with a putative 18-amino acid signal peptide, preceding the 222 amino acids in the mature enzyme, indicating that the enzyme is a secretory protein. The first 95 amino acids of the mature enzyme show no sequence homology with other sequenced proteins and there is one possible N-glycosylation site (Asn-89). The amino acid sequence from residues 96-193 shows strong homology (approximately 50%) with the final two-thirds of the sequences of all known eukaryotic CuZn SODs, whereas the homology with the P. leiognathi CuZn SOD is clearly lower. The ligands to Cu and Zn, the cysteines forming the intrasubunit disulfide bridge in the CuZn SODs, and the arginine found in all CuZn SODs in the entrance to the active site can all be identified in EC-SOD. A comparison with bovine CuZn SOD, the three-dimensional structure of which is known, reveals that the homologies occur in the active site and the divergences are in the part constituting the subunit contact area in CuZn SOD. Amino acid sequence 194-222 in the carboxyl-terminal end of EC-SOD is strongly hydrophilic and contains nine amino acids with a positive charge. This sequence probably confers the affinity of EC-SOD for heparin and heparan sulfate. An analysis of the amino acid sequence homologies with CuZn SODs from various species indicates that the EC-SODs may have evolved from the CuZn SODs before the evolution of fungi and plants.     

Ixodes ricinus spirochete infection as the cause of postinfectious arthritis in Sweden

Antibodies to Swedish Ixodes ricinus spirochete were determined by an enzyme-linked immunosorbent assay (ELISA) in sera from 298 patients with postinfectious arthritis. Sera from healthy individuals, patients with acute infectious meningitis of proven etiology and patients with multiple sclerosis served as controls. With the upper limit of normal values set at the 95 percentile of controls, 18 of 298 (6%) arthritis patients had positive serum antibody titres. Titres above the 100 percentile of controls were found in 5 of 298 (2%) arthritis patients. Two of the arthritis patients had extremely high titres--higher than any earlier found in Swedish patients with spirochetal meningitis. The clinical manifestations and laboratory findings in the 5 patients with high spirochetal antibody titres are described. It is concluded that a spirochetal etiology should be considered in patients with reactive or postinfectious arthritis of unknown origin.     

Stimulation of beta-adrenoceptors with isoprenaline inhibits small intestinal activity fronts and induces a postprandial-like motility pattern in humans.

AIMS: To investigate the effects of beta-adrenoceptor stimulation, using the agonist isoprenaline and the antagonist propranolol, on migrating motor complexes in the upper intestine of 16 healthy human volunteers. METHODS: Fasting motility was monitored using a tube with water perfused side holes connected to a pneumohydraulic system. Continuous eight hour recordings were obtained from each volunteer after a 12 hour fasting period. In all experiments, saline was given as control for the first four hour period and beta-adrenergic agents for the next four hours. In separate control studies, saline was given for the whole eight hour period. RESULTS: Isoprenaline (2.5 micrograms/kg/min) reduced the number of activity fronts (phase III) of migrating motor complexes from 3 (2-4) in controls to 1 (0-2) during isoprenaline infusion (p < 0.01). Also, phase II-like activity replaced the regular motility pattern (p < 0.01). By contrast, propranolol (25 micrograms/kg/min) did not induce any significant changes in phase III compared with controls. Saline alone had no effect on motor activity. CONCLUSIONS: Isoprenaline inhibited activity fronts in the human proximal small intestine and induced a postprandial-like motility pattern, whereas propranolol did not affect motor patterns. Stimulation of beta-adrenoceptors is of importance in the control of motor activity of the human small intestine, especially under stressful conditions with high adrenergic activity.     

Lower threshold for adenosine-induced chest pain in patients with angina and normal coronary angiograms

Objective—To investigate whether patients with angina-like chest pain and normal coronary angiograms are more sensitive to adenosine as an inducer of chest pain.

Design—Increasing doses of adenosine were given in a single blind study as intravenous bolus injections. Chest pain and the electrocardioraphic findings were noted.

Patients—Eight patients with anginalike chest pain but no coronary stenoses (group A), nine patients with angina and coronary stenoses (group B), and 16 healthy volunteers (group C).

Results—In the absence of ischaemic signs on the electrocardiogram adenosine provoked angina-like pain in all patients in groups A and B. The pain was located in the chest, and its quality and location were described as being no different from the patient's habitual angina. In group C, 14 of 16 subjects reported chest pain. The lowest dose resulting in chest pain was lower in group A (0·9 (0·6) mg) than in group B (3·1 (1·5) mg) (p < 0·005) and in group C (6·2 (3·7) mg) (p < 0·005). The maximum tolerable dose was lower in group A (4·7 (2·1) mg) than in group B (9·2 (3·8) mg) (p < 0·05) and in group C (12·0 (4·1) mg) (p < 0·005).

Conclusions—Patients with anginalike chest pain and normal coronary angiograms have a low pain threshold and low tolerance to pain induced by adenosine.

     

Nurse-led heart failure clinics improve survival and self-care behaviour in patients with heart failure: results from a prospective, randomised trial.

AIM: The aim of this trial was to prospectively evaluate the effect of follow-up at a nurse-led heart failure clinic on mortality, morbidity and self-care behaviour for patients hospitalised due to heart failure for 12 months after discharge. METHODS: A total of 106 patients were randomly assigned to either follow-up at a nurse-led heart failure clinic or to usual care. The nurse-led heart failure clinic was staffed by specially educated and experienced cardiac nurses, delegated the responsibility for making protocol-led changes in medications. The first follow-up visit was 2-3 weeks after discharge. During the visit the nurse evaluated the heart failure status and the treatment, gave education about heart failure and social support to the patient and his family. RESULTS: There were fewer patients with events (death or admission) after 12 months in the intervention group compared to the control group (29 vs 40, p=0.03) and fewer deaths after 12 months (7 vs 20, p=0.005). The intervention group had fewer admissions (33 vs 56, p=0.047) and days in hospital (350 vs 592, p=0.045) during the first 3 months. After 12 months the intervention was associated with a 55% decrease in admissions/patient/month (0.18 vs 0.40, p=0.06) and fewer days in hospital/patient/month (1.4 vs 3.9, p=0.02). The intervention group had significantly higher self-care scores at 3 and 12 months compared to the control group (p=0.02 and p=0.01). CONCLUSIONS: Follow up after hospitalisation at a nurse-led heart failure clinic can improve survival and self-care behaviour in patients with heart failure as well as reduce the number of events, readmissions and days in hospital.     

Improved fibrinolysis by an intensive lifestyle intervention in subjects with impaired glucose tolerance. The Finnish Diabetes Prevention Study

Aims/hypothesis The aim of this study was to investigate the effects of lifestyle intervention on the levels of plasminogen activator inhibitor (PAI-1) and fibrinogen in subjects participating in the Finnish Diabetes Prevention Study (DPS).Methods In five DPS centres, 321 subjects with impaired glucose tolerance (intervention group, n=163; control group, n=158) had their PAI-1 and fibrinogen levels measured at baseline and at the 1-year follow-up. Additional 3-year follow-up assessments were carried out in a sample of 97 subjects in one of the DPS centres (Turku). The intervention programme included an intensive lifestyle intervention aiming at weight reduction, healthy diet and increased physical activity.Results During the first intervention year, PAI-1 decreased by 31% in the intervention group but showed no change in the control group (p<0.0001). In the Turku subgroup, the decrease in PAI-1 persisted throughout the 3-year follow-up. Changes in PAI-1 were associated with the number of lifestyle changes made during the first year (p=0.008). Weight reduction was the most important factor explaining the decrease in PAI-1. Changes in fibrinogen levels did not differ between the groups.Conclusions/interpretation In addition to the previously reported reduction in the risk of type 2 diabetes in DPS participants with impaired glucose tolerance, the intensive dietary and exercise intervention had beneficial long-term effects on fibrinolysis as indicated by the reduced levels of PAI-1. These results suggest that elevated PAI-1 levels in obese subjects with impaired glucose tolerance are mostly reversible by lifestyle changes, especially those geared to weight reduction.     

Outcome of gastrointestinal complications after liver transplantation for familial amyloidotic polyneuropathy

BACKGROUND: Gastrointestinal disturbances are important prognostic factors for mortality and morbidity after liver transplantation for familial amyloidotic polyneuropathy (FAP). However, the impact of liver transplantation on malabsorption and bacterial small-bowel contamination has not been evaluated. METHODS: Twenty-three FAP patients were available for the study. They were examined for gastrointestinal disturbances as a part of the evaluation for liver transplantation for FAP. Bile acid malabsorption was diagnosed with the [75Se]-homocholic acid taurate (SeHCAT) test; fat malabsorption by measuring faecal fat excretion; and bacterial small-bowel contamination with the hydrogen breath test (HBT). RESULTS: No significant improvement of malabsorption test results were noted from the pre-transplant evaluation 8 months (range, 2-20 months) before transplantation to the post-transplant evaluation performed a median of 20 months (range, 9-62 months) after the procedure. The SeHCAT test result became abnormal in two patients and normal in one, and changes in the test correlated with the time the patients were waiting for transplantation. Faecal fat excretion after transplantation correlated with duration of the disease and with fat excretion before transplantation. A significantly increased fat excretion was noted at the post-transplant evaluation. A change in HBT result was noted in only one patient, in whom the test result became normal; pre-transplant values correlated with those obtained after transplantation. CONCLUSION: For most FAP patients no improvement in gastrointestinal function was found after transplantation. The finding underlines the importance of an early transplantation before the patients have developed gastrointestinal dysfunction.     

The snack is critical for the blood glucose profile during treatment with regular insulin preprandially

OBJECTIVES: To evaluate how a snack influences the blood glucose profile during treatment with preprandial regular human insulin. DESIGN: In a randomized study a mid-morning snack either was or was not served. Insulin was given 30 min before the usual breakfast of the patients. Plasma free insulin and blood glucose were repeatedly determined for 5 h. SETTING: Outpatient clinic at a university hospital. SUBJECTS: Twenty patients with type 1 diabetes treated with multiple injections of regular insulin (Actrapid) and eight non-diabetic subjects. INTERVENTIONS: A mid-morning snack either was or was not served 2 h after the usual morning insulin injection. MAIN OUTCOME MEASURES: A difference in the blood glucose profile after a mid-morning snack. RESULTS: With a snack there was no difference in blood glucose fasting and at 12.30 h, whilst without a snack there was a decrease of almost 4 mmol L-1, several patients experienced low blood glucose and three had hypoglycaemia. An extended peak of free insulin was reached 30 min after the insulin injection with a slow decrease to the fasting level after 5 h. After the insulin injection a significant decrease in blood glucose occurred within 30-45 min. CONCLUSIONS: A snack 2 h after the insulin injection results in a smoother blood glucose profile and reduces the risk of hypoglycaemia in patients with type 1 diabetes treated with preprandial regular human insulin. Furthermore, the recommended interval of 30 min between insulin injection and a meal may be too long.     

Epitope-specific recognition of type II collagen by rheumatoid arthritis antibodies is shared with recognition by antibodies that are arthritogenic in collagen-induced arthritis in the mouse

OBJECTIVE: To analyze the fine specificity of IgG autoantibodies in sera from rheumatoid arthritis (RA) patients for type II collagen (CII) epitopes that are arthritogenic in collagen-induced arthritis (CIA), a relevant murine model of RA. METHODS: For enzyme-linked immunosorbent assay (ELISA) analysis of conformation-dependent autoantibody binding, recombinant chimeric collagens that harbor the respective CII epitopes as an insertion within the frame of a constant type X collagen triple helix were constructed. In addition, synthetic peptides mimicking the native collagen structures were applied for the first time in the ELISA assessment of humoral CII autoimmunity. RESULTS: The pathogenicity of IgG responses to certain CII determinants in CIA was demonstrated by arthritis development in BALB/c mice upon the combined transfer of 2 mouse monoclonal antibodies specific for precisely mapped conformational CII epitopes (amino acid residues 359-369 [C1(III)] and 551-564 [J1]), whereas antibodies to another epitope (F4) were not arthritogenic. To test whether human autoimmune responses are similarly directed to these conserved CII determinants, serum IgG was analyzed. The prevalence of sera with increased IgG binding to the C1(III) epitope was significantly higher in RA compared with sera from healthy donors or from patients with other rheumatic conditions, e.g., osteoarthritis (OA), systemic lupus erythematosus (SLE), or relapsing polychondritis (RP), whereas levels of antibodies specific for the nonarthritogenic F4 epitope were associated with OA rather than RA. CONCLUSION: Autoimmunity to CII, although detectable in different rheumatic conditions, differs in fine specificity between distinct disease entities. In RA, in contrast to degenerative joint disease, RP, and SLE, autoantibody responses are directed to an evolutionary conserved CII structure that is also targeted by pathogenic autoimmune responses in murine models of arthritis.