Activation of transcription by the promoterspecific factor Spl requires coactivators that are tightly associated with the TATA-box-binding protein (TBP) in the TFIID complex. Recent work has shown that the two glutamine-rich activation domains of Spl, A and B, can interact with at least one component of this complex, the TBP-associated factor dTAFH110. Here we report the mapping ofa region of Spl with alternating glutamine and hydrophobic residues which is required for the interaction with dTAFI11O and is important for mediating transcriptional activation. Substitution of bulky hydrophobic residues within this region decreased both interaction with dTAFI11O and transcriptional activation in Drosophika cels. In contrast, mutation ofglutamine residues in this region had no effect. Thus, the strength of the Spl-TAF interaction correlates with the potency of Spl as a transcriptional activator, indicating that this activator-TAF interaction is an important part of the mechanism of btanscriptional activation.,Sequence comparison of three activation domains shown to bind dTAFIl1O suggests that different activators that utilize dTAF]m11O as a coactivator may share common sequence features that we have determined to be important for the Spl-dTAFIl110 interaction.Transcription initiation by RNA polymerase II requires a number of accessory factors,

Objectives We sought to determine the incidence and clinical characteristics of sudden cardiac death (SCD) in patients with HIV. Background As the HIV-infected population ages, cardiovascular disease prevalence and mortality are increasing; however, the incidence and features of SCD have not yet been described. Methods Records of 2860 consecutive patients in a public HIV clinic in San Francisco, CA between April 2000 and August 2009 were examined. Identification of deaths, causes of death, and clinical characteristics were obtained by search of the National Death Index and/or clinic records. SCDs were determined using published retrospective criteria: (1) ICD10 code for all cardiac causes of death and (2) circumstances of death meeting WHO criteria. Results Of 230 deaths over 3.7 median years’ follow-up, 30 (13%) met SCD criteria, 131 (57%) were due to AIDS, 25 (11%) other (natural) diseases, and 44 (19%) overdose/suicides/unknown. SCDs accounted for 86% (30/35) of all cardiac deaths. The mean SCD rate was 2.6 per 1,000 person-years (95%CI 1.8-3.8), 4.5-fold higher than expected. SCDs occurred in older patients than AIDS deaths (mean 49.0 vs. 44.9 years, p=0.02). Compared to AIDS and natural deaths combined, SCDs had higher prevalence of prior MI (17% vs. 1%, p<0.0005), cardiomyopathy (23% vs. 3%, p<0.0005), heart failure (30% vs. 9%, p=0.004), and arrhythmias (20% vs. 3%, p=0.003). Conclusions SCDs account for most cardiac and many non-AIDS natural deaths in HIV-infected patients. Further investigation is needed to ascertain underlying mechanisms, which may include inflammation, antiretroviral therapy interruption, and concomitant medications.

Forty percent of deaths attributed to stated cardiac arrest were not sudden or unexpected, and nearly half of presumed SCDs were not arrhythmic. These findings have implications for the accuracy of SCDs as defined by WHO criteria or emergency medical services records in aggregate mortality data, clinical trials, and cohort studies.

BACKGROUND-A decrease in inflammation after cure of atrial arrhythmias suggests that such arrhythmias are pro-inflammatory, and lower inflammatory marker levels in the coronary sinus suggest that atrial arrhythmias result in the intracardiac appropriation of inflammatory cytokines.

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The adenovirus E1A protein both activates and represses gene expression to promote cellular proliferation and inhibit differentiation. Here we report the identification and characterization of a cellular protein that antagonizes transcriptional activation and cellular transformation by E1A. This protein, termed CREG for cellular repressor of E1A-stimulated genes, shares limited sequence similarity with E1A and binds both the general transcription factor TBP and the tumor suppressor pRb in vitro. In transfection assays, CREG represses transcription and antagonizes 12SE1A-mediated activation of both the adenovirus E2 and cellular hsp70 promoters. CREG also antagonizes E1A-mediated transformation, as expression of CREG reduces the efficiency with which E1A and the oncogene ras cooperate to transform primary cells. Binding sites for E2F, a key transcriptional regulator of cell cycle progression, were found to be required for repression of the adenovirus E2 promoter by CREG, and CREG was shown to inhibit activation by E2F. Since both the adenovirus E1A protein and transcriptional activation by E2F function to promote cellular proliferation, the results presented here suggest that CREG activity may contribute to the transcriptional control of cell growth and differentiation.Studies of the transforming proteins of small DNA tumor viruses, such as adenovirus E1A, simian virus 40 large tumor antigen, or human papillomavirus E7, have revealed a great deal about the proteins and pathways that regulate cellular proliferation. In normal cells, the transition from G 1 to S phase and the start of DNA synthesis is tightly controlled by mechanisms that include transcriptional regulation of genes encoding proteins required in the S phase. In many cell types, the adenovirus E1A protein dramatically alters the transcriptional program of the host cell to stimulate cell division and inhibit differentiation. The ability of E1A to reprogram cellular gene expression to promote entry into S phase correlates with the ability of E1A to cooperate with oncogenes, such as ras, to transform primary cells (38,62).The protein products of both the 12S and 13S mRNA forms of E1A (12SE1A and 13SE1A, respectively) regulate the expression of a number of viral and cellular genes. Although 13SEIA has a unique transcriptional activation domain encoded by CR3, the sequences present in 12SE1A are sufficient to mediate cellular transformation. Investigations into the mechanisms by which E1A activates and represses expression of particular genes have revealed that 12SE1A interacts with several transcriptional regulators of cell proliferation, including the retinoblastoma tumor suppressor protein, pRb, and the coactivators p300 and CBP. Two conserved regions of E1A, CR1 and CR2, have been shown to mediate binding to pRb, and CR1 also participates in binding to p300 (14, 71). The functional importance of these interactions is supported by the observation that mutations in CR1 and CR2 result in E1A proteins defective in transcriptional regulation and cellular t...

BACKGROUND-Regional differences in fibrosis, particularly related to the posterior wall and septum, may be important in atrial fibrillation (AF). Using electroanatomic mapping, voltage can be used as a measure of fibrosis.

Unique scintigraphic parameters for the evaluation of ventricular synchrony were derived, and their added value was determine compared with established measures. Indications for pacemaker therapy now include the treatment of severe congestive heart failure (CHF). Atrial triggered biventricular pacemakers reduce CHF symptoms and prolong life in patients with cardiomyopathy, severe CHF, left ventricular (LV) ejection fraction (EF) lower than 35%, and QRS greater than 120 milliseconds. Such pacing, or cardiac resynchronization therapy (CRT), seeks to reduce the heterogeneity and increase the synchrony of ventricular activation, conduction, and contraction. CRT has improved hemodynamics, increased exercise tolerance, reduced symptoms and the need for hospitalization, reversed ventricular remodeling, and reduced the all-cause mortality rate in CHF. However, CRT is costly, fails to improve symptoms or activity level in more than 30% of patients, and is applied blindly without individualization or consideration of lead placement sight. A variety of echocardiographic methods have sought to measure synchrony and its serial changes with CRT. A recent study presented evidence of the poor reproducibility of several widely applied echocardiographic measurements by which to determine ventricular synchrony. Magnetic resonance imaging has excellent resolution of regional wall motion and has been applied to assess ventricular synchrony and its response to pacing therapy. However, these methods are complex and are not well established or widely available, and magnetic resonance imaging has not been widely applied after pacing. An accurate and reproducible method is needed by which to objectively measure regional ventricular synchrony. Phase image analysis, a functional method based on the first Fourier harmonic fit of the gated blood pool time versus radioactivity curve, generates the parameters of amplitude (A), which parallels the extent of regional ventricular contraction or stroke volume, and phase angle (Ø), which represents the timing of regional contraction. It was applied early with demonstrated reproducibility to show the linkage between electrical and mechanical dyssynchrony and to characterize the contraction pattern in heart failure and its alteration with CRT. The SD of ventricular Ø, applied as a marker of synchrony, has been shown to demonstrate the beneficial effects of biventricular pacing, and its strong prognostic value has been shown in patients with congestive cardiomyopathy and CHF, superior to LVEF. The SD Ø may not be optimal for synchrony evaluation. We sought improved, more sensitive parameters to better differentiate synchrony among the spectrum of possible patterns of dyssynergy. We derived, initially evaluated, and here present new synchrony (S) and entropy (E) parameters, based on the phase method, to quantitate regional and global ventricular synchrony and applied them in simulation and clinical protocols.