S- and C-glycopeptide derivatives of an LH-RH agonist

The S- and C-glycosylated nonapeptides 1 and 2 were synthesized as analogs of the non-glycosylated LH-RH agonist buserelin (pGlu-His-Trp-Ser-Tyr-D-Ser(tBu)-Leu-Arg-Pro-NHEt) by segment condensation in solution. 1 and 2 differ from this peptide in the amino acid in position 6. In the first case (l), D-serine (tBu) is substituted by D-CySteine carrying a rhamnosyl residue, in the second case (2) D-alanine carrying a galactosyl moiety bound as C-glycoside is incorporated. The bioactivity of both glycopeptides as fertility drugs was determined from the dose dependent LH release in male rats. Additionally, in female rats the ovulation rate was assessed. As a result the analog 1 exhibits a similar biological activity as buserelin while analog 2 shows about 25% of this potency. Compared to buserelin the solubility of the analogs 1 and 2 in aqueous buffer is improved by more than two orders of magnitude due to the carbohydrate moieties. © Munksgaard 1996.     

Vibration, Acceleration, Gravitation, and Movement: Activity Controlled Rate Adaptive Pacing During Treadmill Exercise Testing and Daily Life Activities

Activity-based sensors for rate adaptive pacing have been available for several years and now include several different types: vibration; acceleration; gravitation; and movement. However, a systematic comparison evaluating the relative advantages and disadvantages of these various sensors has received little study. The purpose of the present study was to compare these sensor subtypes using treadmill testing and an outdoor test circuit, which simulated daily life activities and included both uphill and downhill walking. Pacemakers were strapped on the chest of healthy volunteers and connected to one channel of an ambulatory recording device, which also recorded the subject's intrinsic heart rate. The pacemakers were programmed using an initial treadmill test to standardize the rate responsive parameters for each device. Nine different pacemaker models were studied including 3 vibration-based (Elite. Synchrony, Metros). 4 acceleration-based (Relay, Excel, Ergos, Trilogy), 1 gravitational-based (Swing), and 1 movement-based (Sensorithm) device. All devices demonstrated a prompt rate response with casual walking on flat ground. The vibration-, gravitational-, and movement-based pacemakers showed a pronounced rate decline during more strenuous work, e.g., walking uphill. This phenomenon was absent in the accelerometer-based units. In particular, the vibration- and movement-based units showed a higher rate with walking downhill compared to uphill. An optimally tuned rote behavior on the treadmill usually did not provide an optimal rate behavior during daily activities and there was a tendency to overstimulation during low workload. The development of the two newest sensors (gravitational and movement) did not result in an improved performance of rate response behavior. Overall, the accelerometer-based pacemakers simulated or paralleled sinus rate behavior the most closely.     

Induced gall-bladder contraction accelerates fragment clearance after extracorporeal shockwave lithotripsy

At the end of extracorporeal shockwave lithotripsy (ESWL) gallstone fragments are dispersed throughout the gall-bladder. In this state they should be expelled more easily than when later sedimented to the gall-bladder fundus. Thus, a randomized study was performed to evaluate the clinical benefit of induced gall-bladder contraction after ESWL. One hundred and five patients with radiolucent gallstones (1–3 stones, diameter ≤ 30 mm) were randomized to received either saline or an infusion of 0.2 μg/kg ceruletide. Stone clearance rates and incidence of biliary symptoms were recorded. Clearance rates at 6 weeks and 3 months after ESWL were significantly (P≤ 0.025) improved by the ceruletide infusion. This effect, resulting in shortened bile acid therapy, was limited to patients with small solitary stones and dependent on a good initial fragmentation. Major side effects attributable to ceruletide were not observed. These results suggest that induced gall-bladder contraction can be successfully applied as an adjuvant treatment in a subgroup of patients with small solitary gallstones.     

Ablation of Atrial Flutter in a Patient with a Tricuspid Valve Replacement after Endocarditis

Myocardial scars from heart surgery are a source of tachycardia, eventually causing late morbidity and sudden death. In general, catheter ablation has been shown to be an effective therapy for various rhythm disorders, but it has been rarely described after atrioventricular valve replacement. We report on a 45-year-old man who developed atrial flutter after implantation of a tricuspid valve bioprosthesis. An electrophysiological investigation revealed typical type-I counterclockwise atrial flutter that was successfully terminated by catheter ablation. A sinus rhythm was restored and remained stable during the course of treatment; the valvular function was not diminished. It is demonstrated that safe mapping and ablation of typical atrial flutter is possible after a tricuspid valve replacement.     

Electrical Performance and Automatic Capture Characteristics of a 3.5-mm2 Passive Fixation Lead during 1-Year Follow-Up

Background: Bipolar low polarization electrodes are recommended for a regular AutoCapture™ (St. Jude Medical, Inc., Sylmar, CA, USA) function in order to effectively detect the evoked response (ER) signal. The objective of this national multicenter registry was to evaluate the electrical performance and the AutoCapture™ characteristics of the bipolar ventricular pacing lead IsoFlex S, model 1636T or 1646T (St. Jude Medical), in combination with single- and dual-chamber pacemakers.
Methods: Ventricular pacing and sensing thresholds, lead impedance, ER amplitude, and polarization signals were measured at discharge and routine follow-up visits after 1, 3, 6, 9, and 12 months. AutoCapture™ activation was recommended based on the results of the ER sensitivity test.
Results: Of the 252 patients initially included, 109 (43%) have completed the follow-up. The mean ventricular pacing threshold was 0.43 ± 0.19 V at discharge and 0.68 ± 0.32 V at 12 months postimplant. The values for the ventricular sensing threshold were between 9.51 ± 4.12 and 9.99 ± 4.09 mV at discharge and at the 12-month follow-up. The unipolar lead impedance decreased from 533 ± 94 to 476 ± 73 ohms during the follow-up. The mean ER amplitude was 16.47 ± 6.70 mV at discharge and 17.42 ± 7.43 mV after 12 months, and the corresponding mean polarization signals were 0.59 ± 1.00 and 0.74 ± 1.24 mV, respectively. AutoCapture™ activation was recommended in at least 95% of the patients investigated over the 12-month follow-up.
Conclusion: The bipolar ventricular pacing lead IsoFlex S 1636/1646T shows a good electrical performance and is mostly compatible with the AutoCapture™ algorithm.     

What Range of Programmable AV Delays is Necessary in Antibradycardia DDD Stimulation?

DDD pacemakers differ considerably in device specific extents of AV delay (AVD) programmability. To demonstrate the requirements of a mean DDD pacemaker patient population optimal AVDs in 200 DDD pacemaker patients (age 8 to 91 years) were estimated by left atrial electrography. The results should help to define an AVD programmability standard. Left atrial electrograms were recorded via a bipolar filtered esophageal lead. The method aims on adjusting the left atrial electrogram to 70 ms prior to the ventricular spike, both during VDD and DDD operation of the pacemaker. In atrial sensed stimulation the optimal AVD varied from 40 to 205 ms (100.5 ± 24.5 ms) and in atrial paced stimulation from 85 to 245 ms (169.1 ±24.5 ms). The difference of the mean values is statistically significant (p < 0.001). The difference between both values in the individual patient, the individual AVD correction time, varied from 0 to 170 ms (68.7 ± 26.6 ms). Thus, from our findings requirements on AV delay programmability standard can be derived: AVDs (1) should have a range from 40 to 250 ms, (2) should be independently programmable during atrial sensed and atrial paced operation, ami (3) should provide as nominal settings 100 ms for atrial sensed and 170 ms for atrial paced stimulation.     

Defibrillation Energy Requirements with Single Endocardial (Endotak™) Lead

The need for thoracotomy in usually high risk patients has limited the use of the implantable cardioverter defibrillator. Initial clinical results with endocardial and subcutanous patch electrodes (SQPs) are en couraging. Using a single endocardial lead in the absence of a SQP for chronic implantation of the cardioverter defibrillator, the goal of the study was to obtain defibrillation thresholds (DFTs) of 15 Joules (J) or less and to investigate changes in DFT over time. We tested 19 consecutive patients (15 men, 4 women] age 62 ± 8.5 years with malignant ventricular arrhythmias (14 VT/5 VF). The underlying heart disease was coronary artery disease in 15 pafients, dilative cardiomyopathy in two patients, and primary electricaJ disease in two patients. Four patients had undergone previous cardiac surgery. Left ventricular ejection fraction ranged between 14% and 66% (39%± 12.6%). Pacing thresholds (0.54 ± 0.17 Vat 0.5 msec), R wave amplitude for pacemaker sensing (14.2 ± 7.0 mV), slew rate (2.12 ± 1.4 V/sec), and resistance (500.3 ± 73.9 W) were sufficient in all patients. Eighteen patients met our endocardial impiant criteria with a DFT ≤ 15 J (10.05 ± 4.03 J) using monophasic (14 patients) or biphasic (four patients) pulse wave forms. In the one remaining patient, with a DFT of 20 J, we implanted a SQP but there was no reduction of the DFT. All patients tested showed successful defibrillation prior to discharge. During follow-up of 88 patient-months (1–9 months), 114 spontaneous VT/VF episodes occurred in five patients and were all successfully terminated. Eleven patients with a minimum follow-up of 2 months were reassessed. In seven out of 11 patients, termination of VF was achieved with the same minimal energy requirements obtained intraoperatively. In three patients, DFT increased by 5 J (one patient) and 10 J (two patients). In a further patient, X ray revealed dislocation of the endocardial lead. Our data suggest that effective defibrillation is feasible with a single endocardial lead for implantation of cardioverter defibrillator. In addition, we strongly recommend repetitive x-ray control to detect asymptomatic lead dislocation. Despite stable DFTs in most of our patients, an energy difference of ≤ 15 J between acute DFT and cardioverter defibrillator energy rating seems to be currently desirable to ensure successful postoperative defibrillation.     

Hepatic and Adrenal Toxicity of a Novel Lipid Regulator in Beagle Dogs

PD 138142-15 is a substituted urea hypolipidemic and potentialanti-atherosclerotic agent. To determine the toxicity of PD138142-15, beagle dogs were given oral doses of 1, 10, 30, and100 mg/kg daily for 13 weeks. Two animals at 100 mg/kg wereeuthanized during Week 5 due to poor condition. Clinical findingsincluded decreased serum albumin at mg/kg, and increased ALP(up to 30-fold) and 5'-nucleotidase activities (up to 9-fold)at doses 10 mg/kg. ALT and AST activities were elevated onlyat 100 mg/kg. There was a two- to threefold increase in cytochromeP450 content of hepatic microsomes from all treated animalsand increases in liver weights at 10 mg/kg and above. Hepaticchanges included hepatocellular hypertrophy and increased cytoplasmiceosinophilia at 10 mg/kg; single cell necrosis of hepatocyteswas noted in moribund animals. ACTH-stimulated cortisol levelswere decreased at 30 and 100 mg/kg. Adrenal cholesterol esterswere decreased at 10 mg/kg and above, while total adrenal cholesterolwas decreased at 30 mg/kg. These changes correlated with adrenalcortical zonal atrophy, principally of the zona fasciculataand zona reticularis, present at 30 and 100 mg/kg. Plasma concentrationsof PD 138142-15 increased with increasing dose; plasma levelswere significantly lower during Week 12 than those on Day 1,possibly due to autoinduction. Overt hepatotoxicity occurredat 100 mg/kg, whereas hepatic changes at 10 and 30 mg/kg wereconsistent with cytochrome P450 induction. The hepatic lesionswere reversible within 4 weeks, while adrenal lesions were stillevident after 4 weeks without treatment.     

Waardenburg Syndrome Type I with Heterochromia Iridis and Circumscribed Hypopigmentation of the Skin

Abstract: We report a 3‐year‐old girl with autosomal dominant inherited Waardenburg syndrome type I showing circumscribed hypopigmentation of the skin, heterochromia iridis, sensorineural deafness, and dental aberrations. Clinical diagnosis was confirmed by the identification of an underlying missense mutation (C811T) in the PAX3 gene. Early diagnosis of Waardenburg syndrome among children with pigment anomalies enables a successful interdisciplinary medical care.