Ibutilide: efficacy and safety in atrial fibrillation and atrial flutter in a general cardiology practice.

BACKGROUND: Published experience with ibutilide (IB) in randomized clinical trials reveals that conversion to sinus rhythm (SR) occurs in 31% of patients with atrial fibrillation (AF) and in 63% of patients with atrial flutter. HYPOTHESIS: The study was undertaken to test the efficacy and safety of IB in patients with AF and with atrial flutter and to compare them with those reported in previous studies. METHODS: In a general cardiology practice, 54 consecutive patients with AF or atrial flutter, no contraindication to IB, and a normal QTc interval, were treated with intravenous IB (0.4-2.0 mg). Duration of arrhythmia, left atrial (LA) size, ejection fraction (EF), time to conversion, QTc interval, and adverse drug events were determined. Patients were observed for a minimum of 6 h. Successful cardioversion was defined as arrhythmia termination within 6 h. RESULTS: Twenty-four of 34 (70.6%) patients with AF and 15 of 20 (75%) patients with atrial flutter converted to SR. Conversion of AF to SR was more likely to occur if duration of AF was approximately 96 h compared with > 96 h (81 vs. 17%, respectively; p = 0.006). The mean time to arrhythmia termination was 68.8 min. Left atrial size, determined by echocardiogram, was 44 +/- 13 mm in 43 patients. Patients with LA size approximately 45 mm had a conversion rate of 55% in both AF and flutter, compared with a conversion rate of 72% in patients with LA size < 45 mm. Ejection fraction was not a predictor of drug success. The QTc intervals were significantly prolonged after IB administration, with a mean change of 47.1 ms for successfully treated patients. Sustained polymorphic ventricular tachycardia occurred in one patient within 1 min of IB infusion, requiring electrical cardioversion to SR. This patient's serum electrolytes and QTc interval were normal prior to IB infusion; however, the QTc increased by 160 ms (from 387 to 547 ms) during drug infusion. No systemic or pulmonary emboli occurred. CONCLUSION: The efficacy of IB for conversion of AF to SR in this prospective observational study was considerably better than previously reported. Duration of AF remains an important predictor of conversion to SR. Complications are rare and without long-term adverse effects.

In vitro properties of the conserved mammalian protein hnRNP D suggest a role in telomere maintenance.

Mammalian chromosomes terminate with a 3' tail which consists of reiterations of the G-rich repeat, d(TTAGGG). The telomeric tail is the primer for replication by telomerase, and it may also invade telomeric duplex DNA to form terminal lariat structures, or T loops. Here we show that the ubiquitous and highly conserved mammalian protein hnRNP D interacts specifically with the G-rich strand of the telomeric repeat. A single gene encodes multiple isoforms of hnRNP D. All isoforms bind comparably to the G-rich strand, and certain isoforms can also bind tightly and specifically to the C-rich telomeric strand. G-rich telomeric sequences readily form structures stabilized by G-G pairing, which can interfere with telomere replication by telomerase. We show that hnRNP D binding to the G-rich strand destabilizes intrastrand G-G pairing and that hnRNP D interacts specifically with telomerase in human cell extracts. This biochemical analysis suggest that hnRNP D could function in vivo to destabilize structures formed by telomeric G-rich tails and facilitate their extension by telomerase.

HuR binding to cytoplasmic mRNA is perturbed by heat shock.

AU-rich elements (AREs) located in the 3' untranslated region target the mRNAs encoding many protooncoproteins, cytokines, and lymphokines for rapid degradation. HuR, a ubiquitously expressed member of the embryonic lethal abnormal vision (ELAV) family of RNA-binding proteins, binds ARE sequences and selectively stabilizes ARE-containing reporter mRNAs when overexpressed in transiently transfected cells. HuR appears predominantly nucleoplasmic but has been shown to shuttle between the nucleus and cytoplasm via a novel shuttling sequence HNS. We report generation of a mouse monoclonal antibody 3A2 that both immunoblots and immunoprecipitates HuR protein; it recognizes an epitope located in the first of HuR's three RNA recognition motifs. This antibody was used to probe HuR interactions with mRNA before and after heat shock, a condition that has been reported to stabilize ARE-containing mRNAs. At 37 degrees C, approximately one-third of the cytoplasmic HuR appears polysome associated, and in vivo UV crosslinking reveals that HuR interactions with poly(A)(+) RNA are predominantly cytoplasmic rather than nuclear. This comprises evidence that HuR directly interacts with mRNA in vivo. After heat shock, 12-15% of HuR accumulates in discrete foci in the cytoplasm, but surprisingly the majority of HuR crosslinks instead to nuclear poly(A)(+) RNA, whose levels are dramatically increased in the stressed cells. This behavior of HuR differs from that of another ARE-binding protein, hnRNP D, which has been implicated as an effector of mRNA decay rather than mRNA stabilization and of the general pre-RNA-binding protein hnRNP A1. We interpret these differences to mean that the temporal association of HuR with ARE-containing mRNAs is different from that of these other two proteins.

Elucidating the mechanism of action of the immunosuppressant 15-deoxyspergualin.

15-Deoxyspergualin (DSG) is an immunosuppressive agent currently in Phase I/II clinical trials. We have previously shown that DSG specifically interacts with Hsc70, a member of the heat shock protein 70 family. In this article we show that DSG appears to bind either kinetically or to a different site on Hsc70 from that of peptides. In addition, we show that DSG inhibits the localization of Hsp70 into the nucleus in response to heat shock. Finally, data are presented showing that there is a correlation between decreases in the transcription factor nuclear factor kappa B and kappa light chain expression in response to varying doses of DSG.