Complement activation and cytokine and chemokines release during mediastinitis

BACKGROUND: Mediastinitis after open heart operation is an infrequent, but life-threatening complication with a reported incidence rate between 1% and 4%. Hospital mortality is estimated at 10% to 35%. The aim of the present work was to study the systemic inflammatory reaction as judged by complement activation and cytokine and chemokines release in patients with mediastinitis after open heart operation. METHODS: Seven patients with clinical signs of mediastinitis were included. Three patients had undergone coronary artery bypass grafting, whereas 4 patients had combined coronary artery bypass grafting, valve replacement, or valvuloplasty. Blood samples were drawn before induction of anesthesia and at the time of reoperation, and thereafter daily during the hospital stay. Controls comprised similar patients with an uneventful postoperative course. RESULTS: The terminal SC5b-9 complement complex concentration in the mediastinitis patients was substantially higher compared with the controls (p < 0.001), and the terminal SC5b-9 complement complex values showed no overlap between the two groups. Interleukin-8, stromal cell-derived factor-1alpha and IL-6 concentrations were also significantly higher in the mediastinitis group than in the control group (p < 0.001), but with considerable overlap between the groups. Interleukin-1beta, interleukin-10, and monocyte chemoattractant protein-1 concentrations were slightly higher in the mediastinitis group, and no differences were seen for the tumor necrosis factor-alpha. CONCLUSIONS: During mediastinitis, the complement is activated and the cytokines and chemokines, interleukin-6, interleukin-8, and stromal cell-derived factor-1alpha are released. These proteins may be involved in the pathogenesis of this complication. Terminal SC5b-9 complement complex may be an indicator to discriminate mediastinitis patients from those with uneventful course.     

P2Y-receptors stimulating the proliferation of human mesangial cells through the MAPK42/44 pathway

1. Mesangial cell proliferation is observed in a number of kidney diseases. The sympathetic cotransmitter ATP is suspected to play a major role in proliferative processes. Therefore, the effects of exogenous ATP on human mesangial cells in culture were studied. 2. Fresh human kidney cortex was processed to obtain mesangial cells in culture. Effects of nucleotides on [(3)H]thymidine incorporation, the activation of mitogen-activated protein kinase and the cell number were studied. The involved P2-receptors were characterized pharmacologically. In addition, we searched for mRNA for P2Y- and P2X-receptors by RT-PCR. 3. ATP (0.1-300 micro M) and related nucleotides induced a significant increase in [(3)H]thymidine incorporation up to 220% of control. The adenine nucleotides ATP and ADP were about equally effective. Also ATP-gamma-S, UTP, ADP-beta-S and 2-m-thio-ADP induced a weaker response. UDP and alpha-beta-methylene-ATP failed to induce an effect on [(3)H]thymidine uptake. 4. ATP (100 micro M) induced a fast activation of the MAPK(42/44) pathway. The effects of ATP on MAPK(42/44) activation and [(3)H]thymidine incorporation were reduced by the MAPK inhibitor PD 98059. Platelet-derived growth factor (PDGF 5 ng ml(-1)) increased the cell number to more than 122% of control. ATP (10 micro M) on top of PDGF amplified PDGF induced cell proliferation to 136% of control. 5. RT-PCR products for P2Y(1,2,4,6,11,12)- and P2X(1,2,4,5,6,7)-receptor subtypes were detected in human mesangial cells. 6. ATP has mitogenic effects on human mesangial cells. DNA synthesis is increased by the activation of the MAPK(42/44) pathway. ATP amplifies PDGF-induced cell hyperplasia.     

Carvedilol blockade of rat myocardial alpha1-adrenoceptors

Carvedilol is a combined alpha(1)- and beta-adrenoceptor antagonist. The ability of carvedilol to antagonize functional effects mediated through myocardial alpha(1)-adrenoceptors has never been investigated. We tested the ability of carvedilol to antagonize the inotropic effect mediated by myocardial alpha(1)-adrenoceptors compared to the antagonism of beta-adrenoceptors. Papillary muscles from rat heart left ventricle were mounted in an organ bath and concentration-response experiments for the inotropic effects of separate alpha(1)- and beta-adrenoceptor stimulation were performed in the absence and presence of carvedilol. Carvedilol antagonized myocardial alpha(1)-adrenoceptors with an inhibition constant (K(i)) of 11.0+/-3.0 nmol/l and the functional experiments were supported by radioligand-binding studies. Corresponding functional studies on the response to beta-adrenoceptor stimulation revealed a K(i) of 1.2+/-0.35 nmol/l. Thus, carvedilol antagonizes the myocardial alpha(1)-adrenoceptors with a 9-fold lower potency than the beta-adrenoceptors. Antagonism of myocardial alpha(1)-adrenoceptor evoked effects may contribute to clinical effects of carvedilol.     

Angiotensin-converting enzyme (ACE) inhibitor therapy after myocardial infarction in relation to left ventricular function

OBJECTIVE: To investigate to what extent and by what methods clinicians assess left ventricular (LV) function after an acute myocardial infarction (AMI) and how the results of the assessments relate to the use of angiotensin-converting enzyme (ACE) inhibitors; furthermore, to explore which main indications caused the clinicians to initiate ACE inhibitor therapy. DESIGN: From 16 hospitals we drew a sample of patients who were discharged with the diagnosis of AMI during a 3-month period in 1999/2000. Physicians in each hospital obtained the observed rate of use of cardiovascular drugs at discharge and also information on ejection fraction (EF) measurements. The results of the EF recordings were classified into three categories: >0.50, 0.40-0.50 and <0.40. The clinicians' main indications for drug use were reported. RESULTS: Among 767 patients discharged alive, EF was measured in 409 (53%), by echocardiography in 53% and by radionuclide ventriculography in 47%. Of the 409 patients 227 (55%) had EF >0.50, 95 (24%) EF 0.40-0.50 and 87 (21%) EF <0.40. Adjusted odds ratio for ACE inhibitor therapy being initiated during the AMI was 13.5 for those with EF <0.40 compared with those with EF >0.50. The main indication for starting ACE inhibitor therapy was heart failure (50%) followed by secondary prevention (42%). CONCLUSION: Measuring EF appears to be an important tool in the evaluation of AMI patients prior to discharge from hospital. Initiation of ACE inhibitor therapy related strongly to the results of the assessments.     

Recurrent thromboembolic events after percutaneous device closure of patent foramen ovale

We report on a 34-year-old male with recurrent transient ischemic attacks 1 year after transcatheter closure of a patent foramen ovale. Echocardiography demonstrated thrombus attached to the device, although the patient had been anticoagulated with phenprocoumon. There was no residual shunt. Computed tomography and transcranial Doppler ultrasonography showed no evidence of a new stroke. The thrombosed device was removed under cardiopulmonary bypass and the defect was closed with a pericardial patch. The patient was discharged home and has been well for almost 2 years. At this time, there is no evidence for any new neurological events.     

Cerebral palsy in Norway: prevalence, subtypes and severity.

BACKGROUND/AIM: To describe prevalence, subtypes and severity of cerebral palsy (CP) in Norway using criteria proposed by the Surveillance of Cerebral Palsy in Europe (SCPE) network. MATERIAL: All children in Norway with CP born in January 1996-December 1998 were registered in the Cerebral Palsy Registry of Norway. The Medical Birth Registry of Norway provided the perinatal data. RESULTS: A total of 374 children with CP were identified with a prevalence of 2.1 per 1000 live births. Detailed information was obtained from 294 (79%) children. Median age at clinical assessment was 6.9 years (range: 1.9-10.2 years). Thirty-three percent of the children had spastic unilateral CP, 49% spastic bilateral, 6% dyskinetic, 5% ataxic CP and 7% were not classified. Severely impaired vision and hearing were present in 5% and 4% of the children, respectively. Active epilepsy was present in 28%, mental retardation in 31% and severely impaired or no speech in 28% children. The most severe impairments in gross motor function were observed in children with low Apgar scores, and the most severe impairments in fine motor function in children born at term, with normal birth weight and low Apgar scores. CONCLUSION: Compared with other populations, the prevalence of CP as well as the proportions of subtypes and gross motor impairments were similar, whereas fine motor impairments and associated impairments were more common. The classification of children with mixed forms of CP is still a challenge. Children were more severely affected if Apgar scores were low, and if they were born at term.     

Influence of CYP2C9 and CYP2D6 polymorphisms on the pharmacokinetics of nateglinide in genotyped healthy volunteers

BACKGROUND: The oral hypoglycaemic drug nateglinide is eliminated from the human body via hepatic biotransformation and renal tubular secretion. According to in vitro data, about 70% of nateglinide intrinsic clearance may be mediated by cytochrome P450 (CYP) 2C9 and a smaller fraction by CYP3A4 and CYP2D6. OBJECTIVE: To assess the impact of CYP2C9 polymorphisms and of the CYP2D6 poor metaboliser genotype on the pharmacokinetics of nateglinide and its effects on insulin, glucose and glucagon in plasma. DESIGN AND PARTICIPANTS: A prospective clinical study in 26 healthy volunteers chosen for their CYP2C9 and CYP2D6 genotype was conducted with individuals carrying wild-type genotype as reference group. METHODS: Serial plasma nateglinide, glucose, insulin and glucagon concentrations were measured over 34 hours after a 180 mg dose of nateglinide under challenge with 75 g of oral glucose at 0, 4 and 8 hours after nateglinide intake. Kinetics were evaluated by nonparametric methods and by population pharmacokinetic-pharmacodynamic modelling. RESULTS: Significantly reduced oral nateglinide clearance was found in carriers of CYP2C9*3 alleles, (p < 0.01), whereas carriers of CYP2C9*2 alleles had kinetic parameters similar to those of carriers of the wild-type allele (p = nonsignificant). Median total clearances were 7.9, 8.4, 6.5, 6.9, 5.8 and 4.1 L/h in carriers of the CYP2C9 genotypes *1/*1, *1/*2, *2/*2, *1/*3, *2/*3 and *3/*3. Median clearance in three carriers of two deficient CYP2D6 alleles was 9.4 L/h. These differences in nateglinide kinetics due to CYP2C9 genotypes did not result in statistically significant differences in plasma glucose, insulin and glucagon. Pharmacokinetic-pharmacodynamic modelling revealed a minor effect of CYP2C9 genotype on insulin and glucose, and extrapolations indicated that carriers of the CYP2C9*3/*3 genotype may be at a slightly higher risk of hypoglycaemia compared with carriers of CYP2C9*1, particularly when taking nateglinide doses above 120 mg. CONCLUSION: The effect of CYP2C9 polymorphisms on nateglinide kinetics may cause a slightly increased risk for hypoglycaemia, which may become relevant in diabetic patients.     

Effect of right atrial overdrive pacing in the prevention of symptomatic paroxysmal atrial fibrillation: a multicenter randomized study,the PAF-PACE study

The aim of this study was to assess if right atrial overdrive pacing can suppress symptomatic episodes of paroxysmal atrial fibrillation (PAF) in patients without bradyarrhythmias. Forty-two patients with frequent and symptomatic PAF without other pacing indication had a pacemaker implanted after a 4-week run-in period, during which the frequency of symptomatic PAF episodes and the mean heart rate were objectively documented. Depending on the mean heart rate recorded during run-in, the pacemaker was programmed in random order to right atrial AAI pacing at 10-19 beats/min > mean heart rate (medium overdrive [MO]), at 20-29 beats/min > mean heart rate (high overdrive [HO]) and to no pacing (OAO mode) for 4-12 weeks each using a crossover design. In the 35 patients who completed the protocol, the number of symptomatic episodes of PAF (>30-second duration) per week was significantly lower during MO pacing (median 0.88, P = 0.001, n = 35) and during HO pacing (median 0.75, P = 0.002, n = 20) than during OAO (median 2.02 and 2.04, respectively). There was no difference between MO and HO pacing in the 20 patients paced at both rates (0.97 vs 0.75, P = 0.33). Seven patients did not complete the protocol due to persistent atrial fibrillation (n = 4), angina pectoris requiring surgery (n = 1), and unwillingness to continue the study due to improvement (n = 1) or worsening (n = 1) of symptoms during the study periods. Right atrial overdrive pacing can reduce the number of symptomatic PAF episodes in patients with frequent and drug refractory PAF but without bradyarrhythmias.     

Radiographic interpretation and treatment decisions among dental therapists and dentists in Western Australia

All dentists and dental therapists employed in the Community Dental Services in Western Australia were invited to participate in a questionnaire study to find out about their use of radiographs and opinions and knowledge about the diagnosis of approximal caries. Replies were received from 45 dentists (95.1%) and 207 dental therapists (84.0%). Most dentists would not restore a lesion before it appeared on radiograph to have reached the dentine, while therapists were more likely to consider a restoration for a lesion just in enamel. Sixty percent of all respondents thought that a cavity was present when the radiographic lesion was confined to enamel. Fifty-seven percent of dentists thought that an average lesion took at least 12 months to progress from outer enamel to dentine, while a majority of dental therapists thought this would take less than 12 months. Radiographs were not frequently taken by the participants. Operators' opinions about cavity formation were the most important predictor of choice of treatment. In general, these participant's responses were similar to those provided by Norwegian and Dutch respondents in similar surveys conducted 5-6 yr ago, but the present participants worked in an optimally fluoridated area and might therefore have been expected to have adopted more cautious criteria for restorative treatment. Differences between dentists and dental therapists were generally not great. The results suggest that calibration of the operators in the service would offer benefits.