Arc suppression Snubbers offer safety in high energy superconducting magnet systems. Large superconducting magnets may have arcing across their breakers at the moment of slow dump initiation ...resulting from a sudden current redistribution in the powering circuit. The ATLAS Experiment at CERN experiences such arcing with its 7.3 H Toroidal magnet powering circuit. To discharge the magnets, the current is redistributed to a parallel branch called the Run Down Unit (RDU) by means of a breaker. Due to the physical layout and other metallic components in the vicinity, the power supply and RDU branches have undesirable and unavoidable parasitic inductance, causing a voltage spike over the main breakers at the moment of opening. The resulting arcing deteriorates the breaker contacts, resulting in increased operating temperatures and a more frequent need for maintenance. The arc suppression system developed takes the form of an RC Snubber (Resistor-Capacitor). The Snubber offers the current a low-impedance path, thus smoothing out the current redistribution and suppressing the voltage spike. This initial charging period of the capacitors gives the current enough time to overcome the parasitic inductance, therefore allowing the RDU to smoothly ramp up without a sudden voltage spike. To test the concept, a 1/50th scale demonstrator was developed and showed successful results. After the demonstrator, endurance testing of the electrolytic capacitors was performed to ensure no degradation of the charging characteristics for an equivalent of 20 years of operation. The Snubber was manufactured and implemented with successful results on the ATLAS Toroidal powering circuit.
Studies of the genetic basis of type 2 diabetes suggest that variation in the calpain-10 gene affects susceptibility to this common disorder, raising the possibility that calpain-sensitive pathways ...may play a role in regulating insulin secretion and/or action. Calpains are ubiquitously expressed cysteine proteases that are thought to regulate a variety of normal cellular functions. Here, we report that short-term (4-h) exposure to the cell-permeable calpain inhibitors calpain inhibitor II and E-64-d increases the insulin secretory response to glucose in mouse pancreatic islets. This dose-dependent effect is observed at glucose concentrations above 8 mmol/l. This effect was also seen with other calpain inhibitors with different mechanisms of action but not with cathepsin inhibitors or other protease inhibitors. Enhancement of insulin secretion with short-term exposure to calpain inhibitors is not mediated by increased responses in intracellular Ca2+ or increased glucose metabolism in islets but by accelerated exocytosis of insulin granules. In muscle strips and adipocytes, exposure to both calpain inhibitor II and E-64-d reduced insulin-mediated glucose transport. Incorporation of glucose into glycogen in muscle also was reduced. These results are consistent with a role for calpains in the regulation of insulin secretion and insulin action.
Abstract Introduction Cardiac resynchronization therapy-defibrillators (CRT-D) are implanted mostly in patients with low left ventricular ejection fraction (LVEF) and wide QRS. In such subjects, ...there is often a concomitant right ventricular (RV) dysfunction, which has been associated with higher long-term mortality. However, data on the association between RV dysfunction and arrhythmic outcomes in patients with CRT-D are scarce. Purpose To define whether there is any association between right ventricular dysfunction and antiarrhythmic therapies or all-cause mortality in patients with HF and CRT-D. Methods The clinical and demographic data of patients enrolled in this study were obtained from the single-centre COMMIT-HF registry. The parameters regarding right ventricular function, such as right ventricle dimension (RVD), tricuspid annular systolic plane systolic excursion (TAPSE) and right ventricular systolic pressure (RVSP) were obtained from electronic patients’ records. The data on the long-term hard endpoints were obtained from the national healthcare provider, while the data on the risk of arrhythmic events, CRT-D shocks and antitachycardia pacing (ATP) were obtained from investigator-initiated and -adjudicated single-centre remote monitoring database updated annually. Multivariable stepwise logistic regression was used to determine independent predictors of the study outcomes, being all-cause death, and the occurrence of appropriate and inappropriate CRT-D therapies. Results During the period between July, 2009 and November, 2019, 335 patients were enrolled at the RM programme after implantation of CRT-D. Of them, during the median (Q1-Q3) follow-up period of 5.3 (2.8-6.6) years, (113 (33.7%) died, 111 (33.1%) received appropriate and 37 (11%) inappropriate therapies. In the multivariable analysis, the independent predictors of all-cause death were reduction in LVEF and increase in RVSP. Lower age and increased LVEDD were independent predictors of appropriate therapies, while lower age and increased RVSP were independent predictors of inappropriate therapies. No association between TAPSE and RVD and outcomes was found. Conclusions Among right ventricular dysfunction parameters, RVSP is an independent predictor of inappropriate therapies and all-cause death, but not of appropriate therapies in patients with HF and CRT-D.
Abstract Introduction Despite improvements in pharmacotherapy and advancements in invasive techniques, patients with ischemic cardiomyopathy are at high risk of adverse events and death. Strategies ...aimed at improving prognosis, including patient-centered individualization of care are needed. Remote monitoring (RM) of patients with heart failure, which allows for a continuous assessment of device- and some patient-related parameters, has been shown to reduce the risk of hospitalization and death, although no analyses were focused specifically on patients with ischemic cardiomyopathy after percutaneous coronary intervention (PCI). Purpose To determine whether RM is associated with outcomes in patients with ischemic cardiomyopathy after percutaneous coronary intervention. Methods The clinical, echocardiographic and angiographic data of consecutive patients with ICM and ICD or CRT-D, who had undergone PCI were obtained from the single-centre COMMIT-HF registry. Each consecutive patient with ICM was offered RM at the discretion of the treating physician. The RM center in our facility monitors patients with cardiac implantable devices in all working days. In case of any clinical, or device-related events potentially requiring reaction, patients are telephonically invited to contact healthcare system, either in the local emergency departments, or in our hospital, or outpatient clinic. Patients supervised with RM undergo routine in-person visits in the outpatient device clinic every 12 months. In the conventional arm, routine visits in the outpatient clinic occur every 6 months. The long-term data were acquired from the National Health Fund – the sole Polish healthcare provider. The primary outcome of the study was 36-month all-cause mortality. Results In the years 2009-2017, there were a total of 1019 patients with ICM and ICD, who underwent PCI, and those constituted the study group. Of those, 227 (22.3%) were monitored remotely, while the remaining were treated conventionally. The studied groups did not differ significantly, apart from that the patients with RM had a history of CABG, and had a lower mean left ventricular ejection fraction (LVEF, 26% vs 32%, p<0.001) than subjects without RM, while the percentage of CRT-D devices was significantly higher in patients with RM (36.2% vs 6.2%, p<0.001). The 36-month all-cause mortality rate was 18.9% in patients monitored remotely and 25.3% in subjects without RM (p log rank = 0.028). In the multivariable analysis, RM was identified as an independent predictor of lower mortality. The other variables independently associated with higher survival were lower age, absence of anemia, optimal glomerular filtration rate, and higher LVEF. Conclusions Remote monitoring of patients with ischemic cardiomyopathy is independently associated with lower all-cause mortality in a real-world cohort of patients with ICDs.Baseline characteristicsMultivariable analysis
Abstract Introduction In patients with atrial fibrillation (AF), an elevated risk of stroke has been demonstrated in the first days after successful electrical cardioversion of AF. Shock therapies ...delivered by implantable cardioverter-defibrillators (ICD) often result in termination of AF, potentially increasing the risk of stroke in those patients. However, the association between ICD shocks and the risk of stroke in patients with AF is unknown. Purpose To define whether there is any temporal association between ICD shocks and strokes in remotely monitored patients with heart failure (HF) and AF. Methods The clinical data of patients enrolled in the remote monitoring (RM) programme after implantation of an ICD were obtained from the single-centre COMMIT-HF registry. The data regarding the occurrence of the first stroke after inclusion to the registry were obtained (based on the International Classification of Diseases codes I63-I64) from the healthcare provider. The RM data of all patients were obtained from the investigator-initiated and -maintained registry of RM, which summarizes all major findings in remotely monitored patients in our department. Each patient with a stroke had the RM history evaluated for the period of the prior 30 days, with emphasis on the last 10 days preceding stroke. Results During the period between 2011 and 2020, 1,299 patients with detailed clinical characteristics were enrolled in the RM programme, and their clinical data are summarized in Table 1.There were 33.4% patients with AF at baseline, and AF de novo was identified during follow-up in further 14.0% of patients. Among patients without and with AF at baseline, respectively 30.9% and 34.1% received any ICD shocks during follow-up (p=NS). In 38.2% of patients without AF at baseline, who developed de novo AF, at least one shock occurred. The median follow-up was 4.4 years, and the incidence of stroke was 45 (3.5%) in the studied population, with a rate of stroke of 2.8% (25/865) in patients without AF at baseline and 4.6% (20/434) in patients with AF (p=NS), as presented in Figure 1. The median (Q1-Q3) time from ICD implantation to stroke was 1.5 (0.8-2.5) years. Strokes occurring less than 10 days from ICD shock were noted in only two patients (0.5% of patients with any ICD shock) and both occurred within 24 hours from the shock. In the first case, the device appropriately terminated ventricular tachycardia which degenerated to ventricular fibrillation after antitachycardia pacing, and in the second case, a shock therapy was delivered due to VF in a 59-year-old male with HF and concomitant paroxysmal AF, who was on chronic treatment with warfarin. Conclusions Our findings indicate an overall low risk of stroke associated with ICD shocks, both in patients with and without AF.Baseline population characteristicsAnalysed population flowchart
Abstract
Funding Acknowledgements
Type of funding sources: None.
Background
The evidence supporting the implantation of implantable cardioverter-defibrillator (ICD) in the primary prevention of ...sudden cardiac death (SCD) comes mostly from the times when optimal management of heart failure was not as effective as at present. Moreover, the detailed data on the long-term risk of arrhythmias in patients with ICD are scarce.
Purpose
To present the long-term results of the remote monitoring (RM) of patients with ICD from a large, tertiary cardiovascular centre registry.
Methods
The clinical data from the time of device implantation were derived from the COMMIT-HF registry, while the follow-up data were obtained from the investigator-initiated RM registry. In brief, the registry encompasses data regarding the types of the transmissions and their contents, with particular emphasis on the occurrence of arrhythmic episodes, device interventions, as well as the data on the causes of other alert transmissions.
Results
In total, 1,299 patients were included in the analysis. The median follow-up duration of RM was 4.4 years, and the primary indication for implantation was ischemic cardiomyopathy (60.3%). Appropriate antitachycardia pacing (ATP) and high-voltage therapy for ventricular arrhythmias occurred in respectively 25.3% and 26.1% of patients, while inappropriate ATP and HV in respectively 11.5% and 8.7%. The prevalence of AF was 40.8%.
Conclusions
In a large real-life cohort of continuously remotely monitored patients with ICDs, the percentage of patients with appropriate therapies for ventricular arrhythmias exceeded 25%. Further analyses are necessary to stratify the risk of ventricular arrhythmias in the contemporary practice.
Baseline characteristics and outcomes
Freedom from ICD therapies during RM
Insulin secretion from the isolated perfused pancreas is characterized by pulses occurring every 5-15 min. The present experiments were performed to explore the role of glucose in regulating these ...pulses. The pancreata from 12 Wistar (W), 12 Zucker diabetic fatty (ZDF), and 6 nondiabetic lean Zucker control (ZC) male rats were isolated and perfused at 37 degrees C with an oxygenated Krebs Ringer solution containing bovine serum albumin and glucose. In W and ZDF, insulin secretion was pulsatile during constant glucose, as assessed by pulse analysis (ULTRA). The pulse period in W was significantly shorter than in ZDF (7.1 +/- 0.6 vs. 14.7 +/- 1.0 min; P < 0.001), whereas the median relative pulse amplitude was not different. When glucose was administered as a series of 10-min sine waves, spectral analysis showed that the normalized spectral power at 10 min was greater in W and ZC compared with ZDF (34.2 +/- 5.9 and 32.9 +/- 2.9 vs. 3.2 +/- 0.9; P < 0.0001), demonstrating entrainment of the insulin pulses to the exogenous glucose oscillations in W and ZC but not in ZDF. Furthermore, in ZDF, the insulin secretory rates were not higher when 28 mM rather than 7 mM glucose were used. In additional studies, islets of Langerhans from one W, three ZDF, and three ZC rats were isolated and perifused using an oscillatory glucose concentration. Single and groups of islets were studied. Islets from diabetic rats demonstrated the same lack of entrainment by glucose seen in the perfused pancreas, suggesting that the defect is at the cellular level. Because these defects bear many similarities to those observed in patients with non-insulin-dependent diabetes mellitus (NIDDM), the ZDF rat appears to represent a good model for beta-cell secretory dysfunction in NIDDM. Additional studies in this model should provide insights into the relative roles of beta-cell dysfunction and insulin resistance in the pathogenesis of the diabetic syndrome.
We examined changes in high- and low-Km glucose phosphorylating activity in pancreatic islet extracts from the prediabetic Zucker diabetic fatty (ZDF) rat between 5-6 weeks and 12 weeks of age (after ...the onset of diabetes). Comparisons were made between the activity observed in the ZDF rat and that seen in the ZDF lean control (ZLC) rat and the obese nondiabetic Zucker fatty (ZF) rat. At 5-6 weeks of age, insulin resistant ZDF and ZF rats were hyperinsulinemic, compared with the ZLC rat, but had normal plasma glucose levels. Kinetic parameters (Vmax and Km for glucose) of hexokinase (HK) and Km of glucokinase (GCK) did not differ between groups. Islet GCK activity for ZDF and ZF rats was 1.7-fold greater than in ZLC rats (P < 0.02 and P < 0.001, respectively). By 12 weeks of age, hypersecretion of insulin at 5.0 mmol/l glucose was observed in perifused islets from both obese groups relative to the ZLC rat. Islets from ZDF rats failed to increase insulin secretion in response to increased glucose concentration. Group differences in the kinetic parameters for GCK or in the Km values for HK were not significant. Islet HK activity for ZDF and ZF rats was 1.9-fold (P < 0.05) and 1.7-fold (P < 0.05) greater, respectively, than for ZLC rats. Compared with the 5- to 6-week-old animals, HK activity increased 3.1-fold (P < 0.001), 2.5-fold (P < 0.002), and 2.0-fold (P < 0.05) for ZDF, ZF, and ZLC rats, respectively. Differences in GCK activity between 5- to 6- and 12-week-old rats were not significant for any of the groups. We conclude: 1) increased islet glucose phosphorylating activity is present in insulin resistant and hyperinsulinemic ZF and ZDF rats, relative to the ZLC rat; 2) at 12 weeks of age, hyperinsulinemic ZDF and ZF rats demonstrated significant increases in HK activity, compared with lean controls; and 3) deficiency in GCK activity does not explain failure of diabetic ZDF islets to respond to glucose, since differences between diabetic ZDF and nondiabetic ZF rats were not statistically significant. Increases in pancreatic islet phosphorylating activity seem to be important in maintaining basal hyperinsulinemia in insulin-resistant animals, but do not appear to play a role in the progression to glucose intolerance and diabetes.
The present study was undertaken to test the hypothesis that exposure to high glucose concentrations enhances insulin secretion in pancreatic islets from glucokinase-deficient mice. Insulin secretion ...and intracellular calcium (Ca2+i) were measured as the glucose concentration was increased from 2 to 26 mmol/l in islets from heterozygous glucokinase (GK)-deficient mice (GK+/-) and their wild-type littermates (GK+/+). Results obtained in islets incubated in 11.6 or 30 mmol/l glucose for 48-96 h were compared. GK+/- islets that had been incubated in 30 mmol/l glucose showed improved although not normal insulin secretory and Ca2+i responses to the standard glucose challenge as well as an enhanced ability to sense small amplitude glucose oscillations. These effects were associated with increased glucokinase activity and protein. In contrast, exposure of GK+/+ islets to 30 mmol/l glucose increased their basal insulin secretion but reduced their incremental secretory responses to glucose and their ability to detect small amplitude glucose oscillations. Thus exposure of GK+/- islets to 30 mmol/l glucose for 48-96 h enhanced their ability to sense and respond to a glucose stimulus, whereas similar exposure of GK+/+ islets induced evidence of beta-cell dysfunction. These findings provide a mechanistic framework for understanding why glucokinase diabetes results in mild hyperglycemia that tends not to increase over time. In addition, the absence of one allele of the glucokinase gene appears to protect against glucose-induced beta-cell dysfunction (glucose toxicity).
To study the natural history of beta-cell dysfunction in an individual who developed insulin-dependent diabetes mellitus (IDDM) over a 13-month period while under observation.
Insulin secretion rates ...(ISR) in response to intravenous glucose and mixed meals were estimated by deconvolution of C-peptide levels.
When fasting glucose and glycosylated hemoglobin concentrations were still within the normal range, insulin secretory responses to intravenous glucose infusion were reduced, but 80- to 100-min secretory oscillations could still be detected. Sequential glucose infusion studies over a 3-month period demonstrated a progressive reduction in insulin secretion. The tight temporal coupling between ultradian oscillations in ISR and glucose observed in nondiabetic subjects was lost. In response to mixed meals, the oscillatory pattern of secretion was preserved, but the magnitude of the secretory responses was reduced.
Our results indicate that despite the lower absolute secretory rates, ultradian ISR oscillations persist in the period before and immediately after the onset of IDDM in this subject, but they are less tightly coupled to glucose than in nondiabetic subjects.
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