Ramipril increases the protein level of skeletal muscle IRS-1 and alters protein tyrosine phosphatase activity in spontaneously hypertensive rats

To investigate mechanisms by which angiotensin converting enzyme (ACE)-inhibition increases insulin sensitivity, spontaneously hypertensive (SH) rats were treated with or without ramipril (1 mg/kg per day) for 12 weeks. Insulin binding and protein levels of insulin receptor substrate-1 (IRS-1), p85-subunit of phosphatidylinositol 3'-kinase (p85) and Src homology 2 domain-containing phosphatase-2 (SHP2) were then determined in hindlimb muscle and liver. Additionally, protein tyrosine phosphatase (PTPase) activities towards immobilized phosphorylated insulin receptor or phosphorylated IRS-1 of membrane (MF) and cytosolic fractions (CF) of these tissues were measured. Ramipril treatment increased IRS-1-protein content in muscle by 31+/-9% (P<0.05). No effects were observed on IRS-1 content in liver or on insulin binding or protein expression of p85 or SHP2 in both tissues. Ramipril treatment also increased dephosphorylation of insulin receptor by muscle CF (22.0+/-1.0%/60 min compared to 16.8+/-1.5%/60 min; P<0.05), and of IRS-1 by liver MF (37.2+/-1.7%/7.5 min compared to 33.8+/-1.7%/7.5 min; P<0.05) and CF (36.8+/-1.0%/7.5 min compared to 33.2+/-1.0%/7.5 min; P<0.05). We conclude that the observed effects of ACE-inhibition by ramipril on the protein expression of IRS-1 and on PTPase activity might contribute to its effect on insulin sensitivity.

Genome-wide association study of intracranial aneurysm identifies three new risk loci

Saccular intracranial aneurysms are balloon-like dilations of the intracranial arterial wall; their hemorrhage commonly results in severe neurologic impairment and death. We report a second genome-wide association study with discovery and replication cohorts from Europe and Japan comprising 5,891 cases and 14,181 controls with approximately 832,000 genotyped and imputed SNPs across discovery cohorts. We identified three new loci showing strong evidence for association with intracranial aneurysms in the combined dataset, including intervals near RBBP8 on 18q11.2 (odds ratio (OR) = 1.22, P = 1.1 x 10(-12)), STARD13-KL on 13q13.1 (OR = 1.20, P = 2.5 x 10(-9)) and a gene-rich region on 10q24.32 (OR = 1.29, P = 1.2 x 10(-9)). We also confirmed prior associations near SOX17 (8q11.23-q12.1; OR = 1.28, P = 1.3 x 10(-12)) and CDKN2A-CDKN2B (9p21.3; OR = 1.31, P = 1.5 x 10(-22)). It is noteworthy that several putative risk genes play a role in cell-cycle progression, potentially affecting the proliferation and senescence of progenitor-cell populations that are responsible for vascular formation and repair.

Factors determining the success of radiofrequency denervation in lumbar facet joint pain: a prospective study

Background and aims Radiofrequency denervation (RF) of the lumbar facet joints has been shown to be effective in well-selected patients. However, long-term success varies between studies. We evaluated the influence of selected psychosocial and constitutional factors on the outcome of RF, expressed as the duration of pain relief. Methods This prospective observational study included 44 patients who received RF denervations at the University Hospital of Berne. Success was defined as at least 50% pain reduction 7–21 days, 6 months and 1 year after RF therapy. The Cox-regression analysis was performed to evaluate the influence of the following factors on the duration of success: age, sex, depression, work inability and previous surgery. Results Complete follow-up was available for 41 patients. The success rate 7–21 days after the denervation was 76%. It decreased to 32% at 6 months and to 22% at 1 year. The median success duration was 17 weeks (95% CI 10–26). The Cox-regression analysis showed a significant shorter duration of success for patients with depression (hazard ratio [HR] 2.97, 95% CI 1.32–6.65), previous surgery (HR 2.39, 95% CI 1.10–5.21) and number of treated joints (HR 1.95 for each increase in the number of joints, 95% CI 1.14–3.33). In bivariate analyses, only depression was kept to be significant. Conclusions Depression seems to be related with a short duration of success. Based on these findings, a comprehensive study is warranted to evaluate whether psychosocial factors have to be considered when recruiting patients for radiofrequency denervation.

Implantation of the biodegradable polymer biolimus-eluting stent in patients with high SYNTAX score is associated with decreased cardiac mortality compared to a permanent polymer sirolimus-eluting stent: two year follow-up results from the "all-comers" LEADERS trial

Background: The SYNTAX score (SXscore) has been shown to be an effective predictor of clinical outcomes in patients undergoing percutaneous coronary intervention (PCI). Methods and results: The SXscore was prospectively collected in 1,397 of the 1,707 patients enrolled in the “all-comers” LEADERS trial (patients post-surgical revascularisation were excluded). Post hoc analysis was performed by stratifying clinical outcomes at two-year follow-up, according to one of three SXscore tertiles: SXlow ≤8 (n=464), 816 (n=472) and SXhigh >16 (n=461). At two-year follow-up the rate of major adverse cardiovascular events was 18.4%, 12.0% and 9.4% in the SXhigh, SXmid, and SXlow tertile, respectively (HR 1.45; CI 1.21-1.74; p<0.01). There was a significantly higher rate of cardiac death in patients in the highest SXscore tertile (7% SXhigh versus 2.4% SXmid versus 1.8% SXlow; HR 2.22; CI 1.5-3.27; p<0.001). Within the SXhigh tertile the rate of cardiac death was significantly lower in patients treated with the biolimus-eluting stent compared with the sirolimus-eluting stent (4.7% versus 9.6%, HR 0.48; CI 0.23-0.99; p=0.046). Conclusions: The SXscore when applied to an “all-comers” patient population allows for prospective risk stratification of patients undergoing PCI up to two years follow-up. In addition, the SXscore appears to separate the performance of devices in high risk patient groups.

Comparison of pro-atrial natriuretic peptide and atrial remodeling in marathon versus non-marathon runners

Long-term endurance sports are associated with atrial remodeling and an increased risk for atrial fibrillation (AF) and atrial flutter. Pro-atrial natriuretic peptide (pro-ANP) is a marker of atrial wall tension and elevated in patients with AF. The aim of this study was to test the hypothesis that atrial remodeling would be perpetuated by repetitive episodes of atrial stretching during strenuous competitions, reflected by elevated levels of pro-ANP. A cross-sectional study was performed on nonelite runners scheduled to participate in the 2010 Grand Prix of Bern, a 10-mile race. Four hundred ninety-two marathon and nonmarathon runners applied for participation, 70 were randomly selected, and 56 entered the final analysis. Subjects were stratified according to former marathon participations: a control group (nonmarathon runners, n = 22), group 1 (1 to 4 marathons, n = 16), and group 2 (≥5 marathons, n = 18). Results were adjusted for age, training years, and average weekly endurance training hours. The mean age was 42 ± 7 years. Compared to the control group, marathon runners in groups 1 and 2 had larger left atria (25 ± 6 vs 30 ± 6 vs 34 ± 7 ml/m(2), p = 0.002) and larger right atria (27 ± 7 vs 31 ± 8 vs 35 ± 5 ml/m(2), p = 0.024). Pro-ANP levels at baseline were higher in marathon runners (1.04 ± 0.38 vs 1.42 ± 0.74 vs 1.67 ± 0.69 nmol/L, p = 0.006). Pro-ANP increased significantly in all groups after the race. In multiple linear regression analysis, marathon participation was an independent predictor of left atrial (β = 0.427, p <0.001) and right atrial (β = 0.395, p = 0.006) remodeling. In conclusion, marathon running was associated with progressive left and right atrial remodeling, possibly induced by repetitive episodes of atrial stretching. The altered left and right atrial substrate may facilitate atrial arrhythmias.

The esophageal ECG as a novel technique for ambulant heart rhythm monitoring

Introduction: Diagnosing arrhythmias by conventional Holter-ECG can be cumbersome because of artifacts, skin irritation and poor P-waves. In contrast, esophageal electrocardiography (eECG) is promising due to the anatomic relationship of the esophagus to the atria and its favorable bioelectric properties. Methods used: In an ambulant setting, we recorded eECGs from 10 volunteers with a novel, highly-miniaturized eECG recorder that is worn discretely behind the ear (1.5×1.8×5cm, 22grams). The device continuously records two eECG leads during 3 days with 500Hz sampling frequency and 24-bit resolution. Results: Mean ± SD recording time was 21.7±19.6 hours (max. 60 hours). Test persons were not limited in daily activities (e.g. eating, speaking) and only complained mild discomfort during probe insertion, which subsided later on. During 99.8% of time, the recorder acquired signals appropriate for further analysis. In unfiltered data, QRS complexes and P-waves were identifiable during >98% of time. P waves had higher amplitudes as compared to surface ECG (0.71 ± 0.42mV vs. 0.16 ± 0.03mV, p = 0.004). No complications occurred. Conclusion: Ambulatory eECG recording is safe, well tolerated and promising due to excellent P-wave detection, overcoming some limitations of conventional Holter ECG.

Nerve excitability changes in critical illness polyneuropathy

Patients in intensive care units frequently suffer muscle weakness and atrophy due to critical illness polyneuropathy (CIP), an axonal neuropathy associated with systemic inflammatory response syndrome and multiple organ failure. CIP is a frequent and serious complication of intensive care that delays weaning from mechanical ventilation and increases mortality. The pathogenesis of CIP is not well understood and no specific therapy is available. The aim of this project was to use nerve excitability testing to investigate the changes in axonal membrane properties occurring in CIP. Ten patients (aged 37-76 years; 7 males, 3 females) were studied with electrophysiologically proven CIP. The median nerve was stimulated at the wrist and compound action potentials were recorded from abductor pollicis brevis muscle. Strength-duration time constant, threshold electrotonus, current-threshold relationship and recovery cycle (refractoriness, superexcitability and late subexcitability) were recorded using a recently described protocol. In eight patients a follow-up investigation was performed. All patients underwent clinical examination and laboratory investigations. Compared with age-matched normal controls (20 subjects; aged 38-79 years; 7 males, 13 females), CIP patients exhibited reduced superexcitability at 7 ms, from -22.3 +/- 1.6% to -7.6 +/- 3.1% (mean +/- SE, P approximately 0.0001) and increased accommodation to depolarizing (P < 0.01) and hyperpolarizing currents (P < 0.01), indicating membrane depolarization. Superexcitability was reduced both in patients with renal failure and without renal failure. In the former, superexcitability correlated with serum potassium (R = 0.88), and late subexcitability was also reduced (as also occurs owing to hyperkalaemia in patients with chronic renal failure). In patients without renal failure, late subexcitability was normal, and the signs of membrane depolarization correlated with raised serum bicarbonate and base excess, indicating compensated respiratory acidosis. It is inferred that motor axons in these CIP patients are depolarized, in part because of raised extracellular potassium, and in part because of hypoperfusion. The chronic membrane depolarization may contribute to the development of neuropathy.

Neuropsychological problems after paediatric stroke: two year follow-up of Swiss children

AIM: The aim of this study was to obtain information about neurological and cognitive outcome for a population-based group of children after paediatric ischaemic stroke. METHODS: Data from the Swiss neuropaediatric stroke registry (SNPSR), from 1.1.2000 to 1.7.2002, including children (AIS 1) and neonates (AIS 2). At 18-24 months after a stroke, a follow-up examination was performed including a history, neurological and neuropsychological assessment. RESULTS: 33/48 children (22 AIS 1, 11 AIS 2) participated in the study. Neurological outcome was good in 16/33. After childhood stroke mean IQ levels were normal (94), but 6 children had IQ < 85 (50-82) and neuropsychological problems were present in 75%. Performance IQ (93) was reduced compared to verbal IQ (101, p = 0.121) due to problems in the domain of processing speed (89.5); auditory short-term memory was especially affected. Effects on school career were common. Outcome was worse in children after right-sided infarction. Children suffering from stroke in mid-childhood had the best prognosis. There was no clear relationship between outcome and localisation of the lesion. After neonatal stroke 7/11 children showed normal development and epilepsy indicated a worse prognosis in the remaining 4. CONCLUSION: After paediatric stroke neuropsychological problems are present in about 75% of children. Younger age at stroke as well as an emergence of epilepsy were predictors for worse prognosis.

Economic evaluation of varicella vaccination in Swiss children and adolescents

This study explores the effects of three different 2-dose varicella zoster virus (VZV) vaccination strategies in Switzerland. The EVITA model was used to assess clinical benefits and costs of strategies (1) vaccination of 11-15 year old adolescents with a negative or uncertain history for chickenpox, (2) universal vaccination of toddlers at age 1 to 2 years, and (3) strategy 2 plus catch-up vaccination of 11-15 year old susceptible adolescents. The cost-effectiveness analysis compares strategies 2 and 3 versus strategy 1 (current vaccination policy in Switzerland). Probabilities for clinical outcomes and medical resource utilization were derived from a real-world survey among Swiss pediatricians and general practitioners including 236 individuals with VZV infection, published information on varicella complications, and expert opinion. Costs of medical resource utilization represent official Swiss medical tariffs. The model predicts both universal childhood vaccination strategies to be more effective in reducing varicella disease burden compared to strategy 1. Economically, both universal childhood vaccination strategies with or without catch-up result in net savings from the societal perspective reflected by a benefit cost ratio (BCR) of 1.22 or 1.29, respectively. In contrast, the model predicts net costs from the payer perspective (BCR of 0.27 and 0.30, respectively). These economic findings are comparable to those reported from other similar evaluations. However, due to the recent recommendation for using a 2-dose varicella vaccination schedule, our economic results for Switzerland are somewhat less favorable than those for other country analyses in which a less expensive 1-dose vaccination regimen for toddlers has been studied.

In vitro comparison of the complement-scavenging capacity of different intravenous immunoglobulin preparations

BACKGROUND AND OBJECTIVES: Complement inhibition is considered important in the mechanism of action of intravenous immunoglobulin (IVIG) in a number of inflammatory and autoimmune disorders. The capacity of different IVIG preparations to 'scavenge' activated C3 and thereby inhibit complement activation was assessed by a new in vitro assay. MATERIALS AND METHODS: Diluted human serum as a complement source, with or without addition of different concentrations of IVIG, was incubated in microtitre plates coated with heat-aggregated human IgG. Complement scavenging was measured by detecting reduced C3 binding and determining fluid phase C3b-IgG complex formation. Complement activation induced by the IVIG preparations was measured as C5a formation. RESULTS: All IVIG preparations exhibited a dose-dependent inhibition of C3b deposition, correlating strongly with binding of C3b to fluid-phase IgG, but the extent of complement scavenging varied considerably between different IVIG preparations. At an IVIG concentration of 0.9 mg/ml, the inhibition of C3b deposition ranged from 72 +/- 16% to 22 +/- 4.1%. The reduction of C3b deposition on the complement-activating surface was not due to IVIG-induced complement activation in the fluid phase, as shown by the low C5a formation in the presence of serum. CONCLUSION: In vitro analysis allows comparison of the complement-inhibitory properties of IVIG preparations. The extent of complement scavenging varies between the products.

Improvement of LaBr3:5%Ce scintillation properties by Li+, Na+, Mg2+, Ca2+, Sr2+, and Ba2+ co-doping

This paper reports on the effects of Li+, Na+, Mg2+, Ca2+, Sr2+, and Ba2+ co-doping on the scintillation properties of LaBr3:5%Ce3+. Pulse-height spectra of various gamma and X-ray sources with energies from 8 keV to 1.33 MeV were measured from which the values of light yield and energy resolution were derived. Sr2+ and Ca2+ co-doped crystals showed excellent energy resolution as compared to standard LaBr3:Ce. The proportionality of the scintillation response to gamma and X-rays of Ca2+, Sr2+, and Ba2+ co-doped samples also considerably improves. The effects of the co-dopants on emission spectra, decay time, and temperature stability of the light yield were studied. Multiple thermoluminescence glow peaks, decrease of the light yield at temperatures below 295 K, and additional long scintillation decay components were observed and related to charge carrier traps appearing in LaBr3:Ce3+ with Ca2+, Sr2+, and Ba2+ co-doping.

Gingival recessions and the change of inclination of mandibular incisors during orthodontic treatment

SUMMARY A recent systematic review demonstrated that, overall, orthodontic treatment might result in a small worsening of periodontal status. The aim of this retrospective study was to test the hypothesis that a change of mandibular incisor inclination promotes development of labial gingival recessions. One hundred and seventy-nine subjects who met the following inclusion criteria were selected: age 11-14 years at start of orthodontic treatment (TS), bonded retainer placed immediately after treatment (T₀), dental casts and lateral cephalograms available pre-treatment (TS), post-treatment (T₀), 2 years post-treatment (T₂), and 5 years post-treatment (T₅). Depending on the change of lower incisor inclination during treatment (ΔInc_Incl), the sample was divided into three groups: Retro (N = 34; ΔInc_Incl ≤ -1 degree), Stable (N = 22; ΔInc_Incl > -1 degree and ≤1 degree), and Pro (N = 123; ΔInc_Incl > 1 degree). Clinical crown heights of mandibular incisors and the presence of gingival recessions in this region were assessed on plaster models. Fisher's exact tests, one-way analysis of variance, and regression models were used for analysis of inter-group differences. The mean increase of clinical crown heights (T₀ to T₅) of mandibular incisors ranged from 0.6 to 0.91 mm in the Retro, Stable, and Pro groups, respectively; the difference was not significant (P = 0.534). At T₅, gingival recessions were present in 8.8, 4.5, and 16.3 per cent patients from the Retro, Stable, and Pro groups, respectively. The difference was not significant (P = 0.265). The change of lower incisors inclination during treatment did not affect development of labial gingival recessions in this patient group.