Genome rearrangements activate the Epstein-Barr virus gene whose product disrupts latency.

A defective Epstein-Barr virus (EBV) containing a deleted and rearranged genome (het DNA) causes latent EBV to replicate. This activity maps to the 2.7-kilobase-pair WZhet fragment. The BZLF1 open reading frame, present within WZhet as well as in the standard viral BamHI Z fragment, encodes the protein ZEBRA, which induces viral replication. Using gene transfers into Burkitt lymphoma cells, we now demonstrate that rearranged sequences juxtaposed to BZLF1 in het DNA facilitate expression of ZEBRA protein. Two stretches of EBV sequences within a palindromic region of het DNA contain positive regulatory elements. One set, derived from the viral large internal repeat, is newly positioned upstream of BZLF1; the second set is downstream of BZLF1 in het DNA. The capacity of defective HR-1 viruses to disrupt latency of the standard EBV genome is due to abnormal regulation of the BZLF1 gene as a result of genomic rearrangements.     

Bolus administration of cladribine in the treatment of Waldenström macroglobulinaemia

This phase II clinical trial evaluated bolus cladribine as a single agent in Waldenström macroglobulinaemia (WM).
Cladribine was administered to 20 patients at a dose of 0.12 mg/kg/d by 2 h intravenous infusion for 5 consecutive days at monthly intervals for three courses. Partially responding patients were continued on therapy until maximal response and/or prohibitive toxicity, to a maximum of eight courses. Complete responders were treated with one additional course of cladribine.
After a median of three courses of cladribine, all 20 patients were evaluable; one achieved a complete response (CR) (5%) and 10 achieved a partial response (PR) (50%). The median duration of response follow-up was 28 months (range 1–37 months). Four of 7 (57%) untreated and 7/13 (54%) previously treated patients responded. The major toxicity encountered was myelosuppression with 60% of patients demonstrating grade 3 or 4 neutropenia. Non-haematological toxicities included two patients with herpes zoster and two patients with non-melanoma skin cancers. At a median follow-up duration of 20 months, 17 patients remain alive and three have died.
We confirm that bolus cladribine is an effective and safe method of drug delivery in WM patients. Recommendations regarding the equivalence of the continuous infusion and bolus methods in untreated patients requires further study. Bolus cladribine is more convenient and less costly than infusional cladribine since it obviates the need for central catheters and infusional devices.     

Depression in sleep disorders clinics

Purpose  The purpose of this paper was to determine the incidence of depression in our sleep disorders clinics (and it’s relation to patient characteristics) and to determine whether the incidence of depression varies in patients with and without sleep apnea. Methods  The Beck Depression Inventory (BDI) was administered to evaluate patients for depression. We reviewed records of all new patients between November, 1995 and May, 1996 and determined their BDI scores and polysomnogram (PSC) results. Patients were divided based on their respiratory disturbance index (RDI); a cut off value of 15 was chosen. Patients were re-divided based on the BDI score (13 or greater suggestive of depression). The age, sex, body mass index (BMI), BDI or RDI (as appropriate) and arousal indices were compared. Results  Sixty-three patients were enrolled; 29% were depressed. BDI scores and PSG data were available in 42 patients. Those with a high RDI had significantly lower BDI scores and higher arousal indices. Those with a high and low BDI scores were not significantly different in any of the parameters evaluated. Conclusions  Symptoms of depression are commonly seen in a sleep clinic. In patients with symptoms suggestive of SA but with low RDI scores, a diagnosis of depression should be entertained. The presence of depression, however, should not negatively influence a decision to perform PSG. Presented in part at the 19th Annual Meeting of the Associated Professional Sleep Societies, Washington, D.C., May, 1996.     

Adjusted-dose continuous-infusion cyclosporin A to prevent graft-versus-host disease following allogeneic bone marrow transplantation

Summary Graft-versus-host disease (GVHD) remains a major obstacle to allogeneic bone marrow transplantation. We administered cyclosporin A (CsA) by continuous intravenous infusion for prophylaxis against GVHD and adjusted the dose to maintain a constant whole blood level. Forty-five patients, ranging in age from 16 to 56, mean 39.5 years, undergoing allogeneic transplantation for various hematological malignancies received CsA as a continuous intravenous infusion. CsA was started on day –1 and continued until day +22 when oral CsA was initiated. The whole blood level of CsA was determined and the dose adjusted to maintain a fixed level. Methotrexate 15 mg/m² i.v. was given on day +1, followed by 10 mg/m² on days +3 and +6. CsA administered as a continuous infusion was well tolerated. All patients required multiple adjustments of the infused dose of CsA to maintain the targeted whole blood level. The mean rise in creatinine was 0.89 mg/dl. There was an association between the concomitant administration of amphotericin B and CsA and the development of nephrotoxicity. Hypertension developed in 30/45 patients, and all responded to oral nifedipine. Tremors were noted in 16/45 patients. None of the patients developed serious neurological side effects. Greater than grade-I acute GVHD developed in only 13% of the patients. We conclude that administering CsA as an adjusted dose by continuous intravenous infusion is well tolerated and effective in preventing acute GVHD in patients undergoing allogeneic bone marrow transplantation.     

The human atrial strength-interval relation. Influence of cycle length and procainamide

We defined the atrial strength-interval relation in 23 patients at cycle lengths of 600, 450, and 300 msec before and after procainamide. The atrial diastolic threshold was similar at cycle lengths of 600 and 450 msec, but the threshold at 300 msec was significantly higher than that determined at 600 and 450 msec both before and after procainamide. Procainamide significantly increased the diastolic threshold only at a cycle length of 300 msec. The strength-interval relation was nonlinear, showing progressively decreasing decrements in the measured refractory period as the stimulating current was increased. Progressive decreases in the drive cycle length from 600 to 450 to 300 msec caused similar decreases in refractory periods. The shape of the curves was similar at cycle lengths of 600 and 450 msex. However, at low current strengths, the slope of the curve determined at 300 msex was significantly more vertical than the slopes of the curves at the longer drive cycle lengths. Procainamide caused similar increases in apparent refractory periods at each paced cycle length. Procainamide did not alter the shape of the curves at any paced cycle length. These observations confirm the importance of stimulation frequency on atrial excitability. They suggest that the effects of procainamide on the effective refractory period of the atrium are not cycle length dependent, although the drug effects on threshold are dependent on the drive cycle length.     

Femoral artery catheterization complications: A study of 503 consecutive patients

This report describes a prospective randomized trial of 503 patients who underwent a cardiac catheterization or interventional procedure at a single institution. In an effort to study femoral complications postprocedure, we evaluated three methods of femoral artery hemostasis as well as 38 variables that were felt to potentially relate to local complications. Only a marginally significant relationship between the hemostasis method and complication rate was found. The factors that contributed to femoral artery complications were: restarting heparin postsheath removal, number of procedures done during one hospitalization, noncompliance of the patient with bedrest after the procedure, number of arterial punctures to initiate the procedure, and preprocedure treatment with corticosteroids.     

Differential effects of hypercapnia on expiratory phases of respiration in the piglet

Hypercapnia induces prolongation of expiratory time (TE) during early development. In the present study, we determined the response to steady state hypercapnia of three neural phases of the total respiratory cycle, inspiration (TI), stage 1 or passive expiration, TE-1 and stage 2 or active expiration, TE-2. Experiments were performed in decerebrate, vagotomized, spontaneously breathing piglets aged 5-10 days. Neural phases of the respiratory cycle were based on electrical activities of the thyroarytenoid (TA, laryngeal adductor) and triangularis sternii (TS, chest wall expiratory muscle) in relation to diaphragm (D) activity. We observed that hypercapnia induced prolongation of both expiratory phases. The greater prolongation of TE-1 was associated with an increase in TA activity and an increase in laryngeal resistance, which peaked early in TE-1, and then progressively decreased. These findings demonstrate that, in early postnatal life, a hypercapnia induced increase in respiratory drive is associated with centrally mediated prolongation of both phases of expiration, a greater prolongation of TE-1, and an increase in laryngeal resistance during post-inspiration. We speculate that the latter serves to optimize gas exchange by reducing large fluctuations in functional residual capacity.     

Ventricular arrhythmias during ergonovine-induced episodes of variant angina

Of 95 consecutive patients with active variant angina who underwent ergonovine testing in the coronary care unit while off treatment, 24 (25%) developed serious ventricular arrhythmias: ventricular tachycardia in eight, bigeminy in seven, pairs in five, and frequent ventricular extrasystoles in four. Ergonovine-induced arrhythmias were observed more often in patients with anterior than inferior ST segment elevation (p less than 0.05). ST segment elevation was significantly higher (10.3 +/- 8.1 vs 3.1 +/- 2.1 mm) in patients who developed arrhythmias. All ventricular arrhythmias began within 3 minutes after the onset of ST segment elevation. The intravenous administration of nitroglycerin eliminated arrhythmias in 22 of 24 cases; in only two patients did ventricular arrhythmias develop after the administration of nitroglycerin. Serious ventricular arrhythmias were found during spontaneous variant angina attacks in 14 of 24 patients with ergonovine-induced arrhythmias compared to 16 of 71 patients without ergonovine-induced arrhythmias (p less than 0.001). We conclude that arrhythmias during ergonovine testing are most often caused by ischemia and not reperfusion. Patients with arrhythmias during ergonovine-induced attacks are more likely to have arrhythmias during spontaneous attacks.     

Improved Risk Stratification for Ventricular Arrhythmias and Sudden Death in Patients With Nonischemic Dilated Cardiomyopathy

BackgroundRisk stratification for ventricular arrhythmias (VA) and sudden death in nonischemic dilated cardiomyopathy (DCM) remains suboptimal.ObjectivesThe goal of this study was to provide an improved risk stratification algorithm for VA and sudden death in DCM.MethodsThis was a retrospective cohort study of consecutive patients with DCM who underwent cardiac magnetic resonance with late gadolinium enhancement (LGE) at 2 tertiary referral centers. The combined arrhythmic endpoint included appropriate implantable cardioverter-defibrillator therapies, sustained ventricular tachycardia, resuscitated cardiac arrest, and sudden death.ResultsIn 1,165 patients with a median follow-up of 36 months, LGE was an independent and strong predictor of the arrhythmic endpoint (hazard ratio: 9.7; p < 0.001). This association was consistent across all strata of left ventricular ejection fraction (LVEF). Epicardial LGE, transmural LGE, and combined septal and free-wall LGE were all associated with heightened risk. A simple algorithm combining LGE and 3 LVEF strata (i.e., ≤20%, 21% to 35%, >35%) was significantly superior to LVEF with the 35% cutoff (Harrell’s C statistic: 0.8 vs. 0.69; area under the curve: 0.82 vs. 0.7; p < 0.001) and reclassified the arrhythmic risk of 34% of patients with DCM. LGE-negative patients with LVEF 21% to 35% had low risk (annual event rate 0.7%), whereas those with high-risk LGE distributions and LVEF >35% had significantly higher risk (annual event rate 3%; p = 0.007).ConclusionsIn a large cohort of patients with DCM, LGE was found to be a significant, consistent, and strong predictor of VA or sudden death. Specific high-risk LGE distributions were identified. A new clinical algorithm integrating LGE and LVEF significantly improved the risk stratification for VA and sudden death, with relevant implications for implantable cardioverter-defibrillator allocation.