Electrophysiologic Effects of the New Class III Antiarrhythmic Drug Dofetilide in an Experimental Canine Model of Pacing-induced Atrial Fibrillation

BACKGROUND: Dofetilide is a new class III antiarrhythmic drug currently under investigation for the treatment of supraventricular arrhythmias in humans. Dofetilide have been previously shown to be highly effective in terminating and suppressing reentrant atrial flutter in the experimental canine crush-injury model, in which its antiarrhythmic efficacy was correlated with prolongation of wavelength and reduction in dispersion of refractoriness, effects not produced by the class IA antiarrhythmic drug quinidine. The purpose of this study was to evaluate the antiarrhythmic efficacy and mechanisms of action of dofetilide in an experimental model of atrial fibrillation. METHODS AND RESULTS: Dofetilide was administered intravenously to seven open-chest dogs with acute sustained atrial fibrillation induced by rapid atrial pacing for up to 4 hours. Mean atrial effective refractory period (ERP), dispersion of ERP, conduction velocity and wave-length were determined by multipoint right atrial programmed stimulation and activation mappin gusing a 56-electrode mapping plaque on the right atrial free wall. Dofetilide prolonged average ERP by 22% from 104 +/- 13 to 127 +/- 15 ms (P <.001), prolonged maximum ERP by 11% from 129 +/- 7 to 143 +/- 10 (P <.003), had no effect on conduction velocity at 200 ms pacing cycle length, slowed conduction velocity by 16% from 0.89 +/- 12 to 0.75 +/-.17 ms at 150 ms pacing cycle length, slowed conduction velocity by 16% from 0.89 +/- 12 to 0.75 +/-.17 ms at 150 ms pacing cycle length (P <.001), increased wavelength by 20% from 93 +/- 7 to 112 +/- 9 mm (P <.01), reduced dispersion of ERP by 24% from 11.4 +/- 2.9 to 8.7 +/- 2.3 (P =.016), and reduced the number of adjacent electrodes with ERP difference >/=20 ms by 67% from 18.4 +/- 7.1 to 6.1 +/- 4.2 (P <.001). Dofetilide reduced the number of excitation wavelets (total over three beats) entering the region of the mapping plaque by 38% from 5.0 +/-.8 to 3.1 +/-.4 (P <.002). Dofetilide terminated atrial fibrillation in all seven dogs at a mean of 3.4 +/- 2.2 minutes into the loading infusion and prevented reinduction of atrial fibrillation in all seven dogs after completion of the loading infusion, while on maintenance infusion. Time to termination of atrial fibrillation correlated closely with change in ERP (r = 0.78, P =.036). CONCLUSIONS: Dofetilide was highly effective in terminating and suppressing sustained pacing induced atrial fibrillation in this canine model. Time to termination of atrial fibrillation correlated with the degree of change in ERP produced by dofetilide. The mechanism of termination of atrial fibrillation by dofetilide appeared to be a progressive reduction and eventual extinction of re-entrant wavelets. The predominant electrophysiologic effects of dofetilide were prolongation of ERP and wavelength and a reduction in dispersion of refractoriness. Dofetilide had little effect on conduction velocity in this model, except at very short pacing cycle lengths.     

Hepatocellular carcinoma in a large Canadian urban centre: Stage at treatment and its potential determinants

OBJECTIVE:

To determine whether there is a significant difference in tumour stage between patients initially found with hepatocellular carcinoma (HCC) at a tertiary hepatobiliary centre and patients referred with tumours detected elsewhere; and to determine variables associated with referral in a palliative stage.

METHODS:

A retrospective review of 12,199 patients seen at a liver clinic over a 10.5-year period revealed 236 patients with HCC first detected internally (internal) and 163 who were referred with a known mass (referred). All patients were staged at the time of treatment using the Milan criteria for transplantation and Barcelona Clinic Liver Cancer (BCLC) staging system. Curative disease was defined as BCLC stages 0 and A. In the referred group, univariate and multivariate analyses were used to determine which of the following factors were significantly associated with presentation in a palliative stage: age, sex, ethnicity, cause of liver disease, presence of cirrhosis, location of residence and quintile of neighbourhood income.

RESULTS:

In comparing the internal versus referred patients, significant differences were found in the proportion of patients fulfilling Milan criteria (72% versus 36%), those with curative disease (75% versus 49%) and those with very early stage tumour (BCLC stage 0, 23% versus 7%); all differences were statistically significant (P<0.001). In patients referred for treatment of HCC from an outside institution, none of the variables tested were associated with presentation in a palliative stage.

CONCLUSION:

Patients with HCC referred to a liver treatment centre were more likely to be in palliative stages than those whose tumour was detected internally.     

Sensitization,pathologic, and imaging findings comparing symptomatic and quiescent failed renal allografts

Late allograft failure (LAF) is a common cause of end stage renal disease. These patients face interrelated challenges regarding immunosuppression management, risk of graft intolerance syndrome (GIS), and sensitization. This retrospective study analyzes sensitization, pathology, imaging, and transfusion requirements in 33 LAFs presenting either with GIS (22) or grafts remaining quiescent (11). All patients underwent immunosuppression weaning to discontinuation at LAF. Profound increases in sensitization were noted for all groups and occurred in the GIS group prior to transplant nephrectomy (TxN). Patients with GIS experienced a major upswing in sensitization at, or before the time of their symptomatic presentation. For both GIS and quiescent grafts, sensitization appeared to be closely linked to immunosuppression withdrawal. Most transfusion naïve patients became highly sensitized. Fourteen patients in the GIS group underwent TxN which revealed grade II acute cellular rejection or worse, with grade 3 chronic active T‐cell‐mediated rejection. Blinded comparisons of computed tomography scan of GIS group revealed swollen allografts with fluid collections compared with the quiescent allografts (QAs), which were shrunken and atrophic. The renal volume on imaging and weight of explants nearly matched. Future studies should focus on interventions to avoid sensitization and GIS.     

Rotational atherectomy with a new device: Initial clinical experience

The Bard Atherectomy Catheter is a new rotational atherectomy device that consists of a flexible, hollow, thin-walled cutting catheter that, while rotated at 1,500 revolutions per minute, is advanced across the lesion over a special spiral guidewire system. We report the initial clinical experience with this device in 20 peripheral lesions in ten patients. The majority of patients were treated for limb salvage. All lesions were successfully intervened on by atherectomy followed by adjunctive balloon angioplasty. A reduction to less than 50% stenosis was achieved in 13 of the 20 lesions (65%) after atherectomy but in all 20 lesions (100%) after adjunctive angioplasty for all lesions and stenting for dissections in two. Baseline minimal lesion lumen diameter was 0.8 ± 0.7 mm with a reference vessel diameter of 4.2 ± 1.7 mm (75 ± 21% stenosis). The lumen improved to 2.0 ± 0.8 mm (45 ± 19% stenosis) (P < 0.001) following atherectomy and to 3.9 ± 1.9 mm (13 ± 16% stenosis) (P < 0.001) after adjunctive angioplasty. The average weight of removed atheroma was 45 ± 58 mg. All ten patients had initial improvement in symptoms. At 6 months follow-up there was persistent improvement in eight patients and two subjects had undergone amputations. Our early clinical experience with this low profile, flexible atherectomy device, that enables extraction of a large amount of atheroma, suggests that it will become a valuable addition to current atherectomy technologies in small- and medium-sized vessels. The value of this device in coronary vessels is under investigation. © 1996 Wiley-Liss, Inc.     

Clinical outcomes following DAA therapy in patients with HCV-related cirrhosis depend on disease severity

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Role of incentives in the training of the frontal EMG relaxation response

Male college students were assigned to a feedback condition in which an auditory signal was correlated with forehead electromyographic (EMG) responses or to a control condition in which a constant low tone was provided. Within each condition, half of the subjects were provided with an incentive for successful reductions of EMG levels from session to session. In the control condition incentives were actually given on the basis of performance of yoked feedback partners. The remaining subjects in each condition (no incentive) were instructed that the incentive was available for reliable participation in the experiment. Feedback subjects acquired lower EMG levels than control subjects, and the yoked-incentive subjects acquired lower levels than no-incentive subjects in the control condition. There were no major differences in EMG levels attributable to locus of control orientation. The results are discussed mainly in terms of implications of incentive variables for reinforcement analyses of biofeedback effects and the validity of the locus of control construct in this application.This research was supported in part by NIMH Special Postdoctoral Fellowship No. MH58202-01 to the first author, sponsored by the Institute of Behavioral Sciences, Honolulu, Hawaii. Computer services were provided by the University of Hawaii Computing Center.Portions of this article were presented at the annual meeting of the Biofeedback Society of America, Albuquerque, New Mexico, 1978.     

The Second Canadian Symposium on Hepatitis C Virus: A call to action

In Canada, hepatitis C virus (HCV) infection results in considerable morbidity, mortality and health-related costs. Within the next three to 10 years, it is expected that tolerable, short-duration (12 to 24 weeks) therapies capable of curing >90% of those who undergo treatment will be approved. Given that most of those already infected are aging and at risk for progressive liver disease, building research-based interdisciplinary prevention, care and treatment capacity is an urgent priority. In an effort to increase the dissemination of knowledge in Canada in this rapidly advancing field, the National CIHR Research Training Program in Hepatitis C (NCRTP-HepC) established an annual interdisciplinary Canadian Symposium on Hepatitis C Virus. The first symposium was held in Montreal, Quebec, in 2012, and the second symposium was held in Victoria, British Columbia, in 2013. The current article presents highlights from the 2013 meeting. It summarizes recent advances in HCV research in Canada and internationally, and presents the consensus of the meeting participants that Canada would benefit from having its own national HCV strategy to identify critical gaps in policies and programs to more effectively address the challenges of expanding HCV screening and treatment.     

Unusual radiographic presentation of IgA nephropathy

An adolescent male presented with hematuria and flank pain. Transient focal renal parenchymal defects were demonstrated by ultrasonography, radionuclide scintigraphy and computed tomography. Renal biopsy revealed IgA nephropathy with acute tubular necrosis. This peculiar radiographic pattern has not, to our knowledge, been previously described in IgA nephropathy and may relate to tubule cell damage by red blood cell casts or patchy renal ischemia.     

Preoperative radiation therapy in clinical stage II endometrial carcinoma.

From 1980 to 1987, 30 patients with FIGO clinical Stage II carcinoma of the endometrium were treated with 5000 cGy preoperative pelvic radiation therapy at Thomas Jefferson University Hospital. Patients with gross cervical disease received additional intracavitary irradiation with a tandem and ovoids for a combined total dose of 7000 cGy to point A. All patients then underwent exploratory laparotomy, total abdominal hysterectomy, and bilateral salpingo-oophorectomy (TAH/BSO). The 5-year actuarial survival for the entire group was 69%. The 5-year actuarial survival for the 8 patients with papillary serous, clear cell, and undifferentiated small cell carcinoma was 38%, with most patients failing in the upper abdomen. The 5-year actuarial survival for the remaining 22 patients was 82%. The only local failure occurred in the patient with an undifferentiated small cell carcinoma. Although preoperative pelvic radiation therapy together with TAH/BSO appears to offer excellent local control in all patients with Stage II endometrial carcinoma, additional treatment options should be considered for patients with papillary serous and clear cell histologies because of the poor survival and high failure rate in the upper abdomen.