Random coil conformation for extended polyglutamine stretches in aqueous soluble monomeric peptides

Several neurodegenerative diseases have been found to be strongly associated with proteins containing a polyglutamine stretch which is greatly expanded from approximately 20 glutamines in normal individuals to more than 40 in affected individuals. A conformational change in the expanded polyglutamine stretch has been suggested to form the molecular basis for disease onset. Model peptides containing polyglutamine tend to aggregate and become insoluble. We have synthesized readily water-soluble monomeric peptides by flanking polyglutamine stretches with sequences rich in alanine and lysine. Circular dichroism measurements show that polyglutamine stretches of length 9 or 17 adopt a random coil configuration in aqueous solution. We think that in the disease-associated peptides for normal individuals the stretches of ～20 glutamines are in a random coil conformation, whereas in affected individuals the polyglutamine stretch may be in some other conformation. Our method to design soluble monomeric peptides containing extended polyglutamine stretches may be generally useful in studying other highly aggregating peptides.     

Effect of Pentaphasic Pulse Sequence as an Impedance Sensor on Standard Electrocardiographic Recordings

Two advances in cardiac pacing have resulted in an internal conflict in some pacemakers. One is the development of a standard lead physiological sensor and the other is protection from electromagnetic interference (EMI). One popular type of standard lead sensor uses sub-threshold pulses to measure intracardiac and intrathoracic impedance changes, i.e., minute ventilation. Recent clinical observations and extensive in vitro testing have verified that digital cellular phones can be troublesome. Large feedthrough capacitors (FCs), effective in blocking the EMI, will preclude sensing of the standard impedance-based signals. A variety of pulse configurations were studied that might be effective for a sensor-based impedance signal while allowing the pacemaker to continue to use large Fcs protecting them from environmental EMI. In comparison to both monophasic and biphasic pulse sequences, a pentaphasic pulse sequence was effective as an impedance sensor, still allows large FCs to function as an effective filter for environmental EMI, and would not produce artifacts on surface ECG.     

Transcranial Doppler Quantification of Residual Shunt after Percutaneous Patent Foramen Ovale Closure. Comparison of Two Devices

Background: Recurrent paradoxical embolism after catheter‐based closure of right‐to‐left shunt (RLS) can be related to residual RLS. To improve closure success, we need a better understanding of the anatomic and device‐related factors associated with closure efficacy. Methods: Patients with cryptogenic neurologic events and severe RLS (Valsalva Spencer transcranial Doppler [TCD] grade 5/5+) who underwent patent foramen ovale (PFO) closure by either central pin (Amplatzer^® PFO [A‐PFO]) or central occluding (Amplatzer^® SO [A‐SO]) devices were evaluated for residual shunt by quantitative TCD evaluation at 3 months. The findings were correlated with atrial septal aneurysm (ASA), device type, and device size. Results: We closed 628 consecutive patients with either the A‐PFO (n = 327) or A‐SO (n = 301) device. The frequency of large defects, small defects, and ASA was 12%, 88%, and 44% of cases, respectively. Severe residual shunt was detected in 13% of A‐PFO and 7% of A‐SO recipients (P = 0.005). This difference was attributable to a much higher frequency of severe residual shunt among patients with large defects closed with the A‐PFO compared to the A‐SO device (12 out of 29 [41%] vs. 3 out of 42 [7%], respectively; P < 0.001). There was no significant difference in device failure frequency for small defects. The presence of ASA increased the frequency of severe residual shunt compared to those without this feature (36 out of 275 [13%] vs. 28 out of 353 [8%], respectively; P = 0.046) but did not influence device‐related differences. Conclusions: (1) Both noncentering and central occluding closure devices effectively reduce RLS after PFO closure. (2) Large PFO defects with or without ASA have lower residual shunt grades at 3 months when closed by central occluding devices. (J Interven Cardiol 2010;23:575–580)     

A Prospective Study Evaluating the Role of Obesity and Obstructive Sleep Apnea for Outcomes After Catheter Ablation of Atrial Fibrillation

Effect of Obesity and OSA on Outcomes Post AF Ablation . Background: Obesity and obstructive sleep apnea (OSA) have a strong association with atrial fibrillation (AF). The purpose of this study was to prospectively determine the effects of obesity, assessed by the body mass index (BMI) and OSA on the efficacy of catheter ablation of AF. Methods: The patient population consisted of 109 patients (mean age: 60 ± 10 years, 79% male, 67% paroxysmal, mean BMI 28 ± 5 kg/m²) who underwent catheter ablation of AF. Based on BMI, patients were classified as normal (<25 kg/m²), overweight (≥25 and <30 kg/m²), or obese (≥30 kg/m²). OSA was assessed by the Berlin questionnaire. Clinical success was defined as at least 90% reduction in AF burden after 3‐month blanking period. Mean duration of follow‐up was 11 ± 4 months. Results: Of the 75 patients with clinical success, 25 (33%) had normal BMI, 29 (39%) were overweight, and 21 (28%) were obese. Among the 34 patients with failed outcome, 5 (15%) had normal BMI, 14 (41%) were overweight, and 15 (44%) were obese (P = 0.04). Twenty‐eight of the 48 patients with OSA (58%) had clinical success as opposed to 47 of the 61 patients (77%) without OSA (P = 0.036). On multivariate analysis, only BMI emerged as an independent predictor of procedural failure ((OR 1.11, CI: 1.00–1.21, P = 0.03). Conclusions: The results of this prospective study show that obesity, a modifiable risk factor, is an independent predictor of procedural failure after catheter ablation of AF. Whether treating obesity may improve the results of catheter ablation of AF warrants further investigation. (J Cardiovasc Electrophysiol, Vol. 21, pp. 521‐525, May 2010)     

Palliative treatment of malignant ascites by intraperitoneal bleomycin after dialytic ultrafiltration with haemofilter

Dialytic ultrafiltration with haemofilter was performed in 16 patients with malignant ascites refractory to treatment with sodium restriction, diuretic and systemic chemotherapy. A continuous flow of ascitic fluid at a rate of 300–400 ml/min through a haemofilter was maintained by a blood pump. The protein-rich ascitic fluid was re-infused into the peritoneal cavity with sodium and water removed. An average of 5.2 1 of filtrate was removed over a mean interval of 3.5 h. Bleomycin (60 mg) was administered intraperitoneally following the procedure. Complete response was observed in six patients (37.25%) and partial response occurred in four (25%). The remaining patients showed no response. Complications of the dialytic ultrafiltration procedure and toxicity of intraperitoneal administration of bleomycin were minimal. The technique of dialytic ultrafiltration is simple, safe and cost-effective and could be used as an adjuvant therapy for intraperitoneal chemotherapy.     

Mucosal pharmacokinetics and pilot study of short course of parenteral imipenem in the eradication of Helicobacter pylori

Abstract Eradication of Helicobacter pylori infection is known to reduce the incidence of duodenal ulcer recurrence. The most commonly used regimen for H. pylori infection is triple antimicrobial therapy for 1-2 weeks. This treatment is associated with frequent side effects and hence unsatisfactory compliance. As in vitro data showed that H. pylori is sensitive to imipenem, the pharmacokinetics of this drug in the gastric milieu, and the clinical efficacy of imipenem with omeprazole in eradicating H. pylori infection were studied. Imipenem/cilastatin levels in serum, gastric secretion and gastric mucosa were assayed in four patients after intravenous injection of a bolus dose of 500 mg. The serum and gastric secretion levels of imipenem achieved were more than 10 times the minimum inhibitory concentration of the drug for H. pylori. Gastric mucosal levels of imipenem vary considerably with time, which probably indicates rapid elimination of the drug into the gastric lumen. In the second part of this study, imipenem/cilastatin was given intravenously for the first 2 days after diagnosis of H. pylori infection in patients with endoscopically confirmed duodenal ulcers. The patients were also treated with 4 weeks of omeprazole. Clearance of H. pylori was initially achieved at the end of 2 days in 20 out of 22 (91%) patients. However, when the biopsies were repeated at 8 weeks, recurrence of H. pylori infection was evident in 19 cases (86.3%) indicating a failure of eradication. It was concluded that imipenem/cilastatin in combination with omeprazole failed to eradicate H. pylori infection.     

Understanding the pathogenesis of type 2 diabetes: can we get off the metabolic merry-go-rounds?

The aetiology of non-insulin-dependent diabetes mellitus (NIDDM) is not known. The concordance of NIDDM in identical twins and differences in the prevalence rate of NIDDM between different racial groups suggest a genetic cause. Hyperglycaemia in established diabetes is caused by a combination of hepatic insulin resistance, impaired peripheral (muscle and fat) glucose uptake and a defect in glucose-mediated insulin secretion. However, it is not known if these defects are all inherited or if one can cause the others. This uncertainty is due to the fact that hyperglycaemia per se can cause defects in insulin action and insulin secretion that resemble those found in NIDDM. Furthermore the elevated free fatty acid (FFA) levels found when NIDDM is associated with obesity are known to cause both peripheral and hepatic insulin resistance. Recently we have demonstrated the mechanism by which elevated FFA levels can cause hepatic insulin resistance. However, we also have evidence that the converse holds in that genetically engineered hepatic insulin resistance in a transgenic rat model leads to obesity. Thus an understanding of the pathogenesis of NIDDM is complicated by the fact that hyperglycaemia and obesity can be both causes and consequences of insulin resistance. To overcome these difficulties, studies in young, euglycaemic diabetes-prone subjects have been conducted. Results suggest that there may be different causes for NIDDM in different racial groups.     

Reproducible Induction of "Atypical" Torsades de Pointes by Programmed Electrical Stimulation:

Sotalol-Induced Polymorphic VT. We present a patient with sotalol-induced polymorphic ventricular tachycardia that was seen only with programmed ventricular stimulation. Electrophysiologic studies performed prior to initiation of sotalol therapy revealed inducible monomorphic ventricular tachycardia. Possible underlying electrophysiologic mechanisms are discussed.