Modulating effects of age and gender on the clinical course of long QT syndrome by genotype

OBJECTIVES: We aimed to determine whether long QT syndrome (LQTS) genotype has a differential effect on clinical course of disease in male and female children and adults after adjustment for QTc duration. BACKGROUND: Genotype influences clinical course of the LQTS; however, data on the effect of age and gender on this association are limited. METHODS: The LQTS genotype, QTc duration, and follow-up were determined in 243 cases of LQTS caused by the KCNQ1 potassium channel gene mutations (LQT1), 209 cases of LQTS caused by the HERG potassium channel gene mutations (LQT2), and 81 cases of LQTS caused by the SCN5A sodium channel gene mutation (LQT3) gene carriers. The probability of cardiac events (syncope, aborted cardiac arrest, or sudden death) was analyzed by genotype, gender, and age (children < or = 15 years and adults 16 to 40 years). In addition, the risk of sudden death and lethality of cardiac events were evaluated in 1,075 LQT1, 976 LQT2, and 324 LQT3 family members from families with known genotype. RESULTS: During childhood, the risk of cardiac events was significantly higher in LQT1 males than in LQT1 females (hazard ratio [HR] = 1.72), whereas there was no significant gender-related difference in the risk of cardiac events among LQT2 and LQT3 carriers. During adulthood, LQT2 females (HR = 3.71) and LQT1 females (HR = 3.35) had a significantly higher risk of cardiac events than respective males. The lethality of cardiac events was highest in LQT3 males and females (19% and 18%), and higher in LQT1 and LQT2 males (5% and 6%) than in LQT1 and LQT2 females (2% for both). CONCLUSIONS; Age and gender have different, genotype-specific modulating effects on the probability of cardiac events and electrocardiographic presentation in LQT1 and LQT2 patients.     

Concurrent chemoradiation strategies in the management of unresectable stage III non-small-cell lung cancer

Locally advanced or unresectable stage III non-small-cell lung cancer (NSCLC) patients treated with combined-modality therapy with chemotherapy plus thoracic radiation have improved survival compared to those treated with radiotherapy alone. Furthermore, recent studies in good performance status, stage III patients have shown that concurrent chemoradiotherapy improves survival compared to sequential chemoradiotherapy. However, the optimal chemoradiation approach continues to evolve and is the subject of this review. Since the majority of patients completing chemoradiotherapy will succumb to distant metastatic disease, active systemic agents targeting this tumor compartment are required. Recent data suggest that full-dose chemotherapy designed to eradicate distant micrometastases given either as induction or consolidation has the potential to yield improved patient outcomes. Many of these chemotherapeutic agents are also potent radiosensitizers, hence providing enhanced local control. The integration of these chemotherapeutic agents into chemoradiotherapy programs in stage III NSCLC is the focus of current trials. Ongoing research with novel therapeutic agents with activity against distant micrometastases, refined radiation techniques, and enhanced imaging methodologies to aid in accurate staging are being pursued and should lead to improved survival and toxicity outcomes in this disease.     

Clinical evaluation of a policy of early repeated internal cardioversion for recurrence of atrial fibrillation

INTRODUCTION: The clinical value of cardioversion (CV) of persistent atrial fibrillation (AF) is limited by the high rate of early AF recurrence, which may be related to the persistence of atrial electrical remodeling. We examined the hypothesis that the likelihood of maintaining sinus rhythm after CV of persistent AF is significantly enhanced by a policy of early repeated CV. METHODS AND RESULTS: Fifty-nine patients with persistent AF underwent internal CV (CV 1). Those patients cardioverted were monitored with daily transtelephonic ECG. In the event of AF recurrence, these patients were admitted rapidly for repeat CV (CV 2) and, if further recurrence occurred, a third CV (CV 3) was performed. Daily ECG monitoring was continued until 1 month of sinus rhythm was maintained or a total of three CVs were performed. Of the 59 patients undergoing CV 1, 43 were discharged in sinus rhythm and 29 subsequently had AF recurrence during monitoring. Twenty-three of these underwent CV 2 and 11 of these underwent CV 3. Of those having repeated CVs, only 4 patients maintained sinus rhythm for 1 month (3 after CV 2 and 1 after CV 3). The remaining patients had repeated AF recurrence during the monitoring period. Mean time from AF recurrence to CV 2 was 20+/-13 hours and from AF recurrence to CV 3 was 13+/-7.2 hours. Atrial effective refractory periods increased from 189+/-16 msec at CV 1 to 215+/-18 msec at CV 3 (P < 0.05), indicating reversal of atrial electrical remodeling during this period. CONCLUSION: A policy of early repeated CVs for AF recurrence has very limited clinical value despite evidence of reversal of atrial electrical remodeling. The time between AF recurrence and repeat CV may need to be reduced further if such a policy is to succeed.     

Computer-assisted image analysis of bronchioloalveolar carcinoma

In clinical trials, response rate is an important endpoint for assessing the efficacy of an anticancer drug. The Response Evaluation Criteria for Solid Tumors (RECIST) has been widely used as a standard method to assess response. The RECIST requires only 1-dimensional measurement of tumor size. However, bronchioloalveolar carcinoma (BAC), which commonly presents as infiltrative or micronodular lesions, is not always readily assessable by RECIST. During the past 2 years, we have been developing computer-based programs to more accurately measure tumor size on chest computed tomography (CT) scans. In a first-generation computer-assisted image analysis (CAIA) system, we were able to capture and quantify lesions on CT scans by linking the software programs of eFilm, HyperSnap, and Scion. We have applied this CAIA approach to measuring BAC response to gefitinib in the Southwest Oncology Group (S0126) trial. However, this first-generation CAIA system involves multiple manual steps and is therefore labor intensive. We are now developing a fully automated CAIA program based on a versatile software platform, ImageJ, created at the National Institutes of Health. Taking theoretical and physical considerations into account, Java plug-in programs for ImageJ are created to automatically analyze CT scans in the Digital Imaging and Communications in Medicine format. We have demonstrated the feasibility of an ImageJ-based automated CAIA program for measuring BAC bidimensionally on CT scans. This automated CAIA system will be applied in a prospective clinical trial of the GVAX vaccine in patients with BAC.     

Current status of antireflux surgery

This article summarizes the historical aspects of antireflux surgery,including the initial techniques and subsequent modifications.Appropriate patient selection is essential to the success of antireflux procedures. The authors review the diagnostic evaluation, the technical details of the procedure, and how to manage surgical failures.     

Effects of intermittent hypoxia on sympathetic activity and blood pressure in humans

Sympathetic nerve activity and arterial pressure are frequently elevated in patients with obstructive sleep apnea (OSA). The mechanisms responsible for chronic sympathetic activation and hypertension in OSA are unknown. To determine whether repetitive apneas raise sympathetic nerve activity and/or arterial pressure, awake and healthy young subjects performed voluntary end-expiratory apneas for 20 s per min for 30 min (room air apneas). To accentuate intermittent hypoxia, in a separate group of subjects, hypoxic gas (inspired O2 10%) was added to the inspiratory port for 20 s before each apnea (hypoxic apneas). Mean arterial pressure (MAP) and muscle sympathetic nerve activity (MSNA, peroneal microneurography) were determined before and up to 30 min following the repetitive apneas. Following 30 hypoxic apneas (O2 saturation nadir 83.1+/-1.2%), MSNA increased from 17.4+/-2.7 to 23.4+/-2.5 bursts/min and from 164+/-28 to 240+/-35 arbitrary units respectively (P<0.01 for both; n=10) and remained elevated while MAP increased transiently from 80.5+/-3.7 to 83.1+/-3.9 mm Hg (P<0.05; n=11). In contrast, in the subjects who performed repetitive apneas during room air exposure (O2 saturation nadir 95.1+/-0.8%), MAP and MSNA did not change (n=8). End-tidal CO2 post-apnea, an index of apnea-induced hypercapnia, was similar in the 2 groups. In a separate control group, no effect of time on MAP or MSNA was noted (n=7). Thus, repetitive hypoxic apneas result in sustained sympathetic activation and a transient elevation of blood pressure. These effects appear to be due to intermittent hypoxia and may play a role in the sympathetic activation and hypertension in OSA.     

Temporal encoding in fear conditioning revealed through associative reflex facilitation

Temporal encoding in Pavlovian fear conditioning was examined through conditional facilitation of the short-latency (Rl) component of the rat eyeblink reflex. Rats were fear-conditioned to a tone conditional stimulus (CS) with either a 3- or 9-s interstimulus interval (ISI) between CS onset and the onset of the grid-shock unconditional stimulus (US). Rl facilitation was tested over 2 days, in counterbalanced order, at a latency of 3 s and 9 s from CS onset. CS-produced Rl facilitation, the conditional response (CR), was 3-4 times larger when the test latency equaled the conditioning ISI. These results, coupled with the known neurophysiology of Rl facilitation, suggest that this CR could disclose differences in the time course of CS-generated output from the amygdala when driven by cortical versus subcortical CS-CR pathways.     

Leucoisoprenochrome-o-semiquinone formation in freshly isolated adult rat cardiomyocytes

Sustained high levels of circulating catecholamines can lead to cardiotoxicity. There is increasing evidence that this process may result from metal-catalyzed catecholamine oxidation into semiquinones, quinones, and aminochromes. We have previously shown that Cu2+-induced oxidation of isoproterenol into isoprenochrome induces toxic effects in isolated cardiomyocytes. The aim of this study was to characterize the isoproterenol oxidation process and to locate the formation of semiquinone radicals in cardiomyocyte suspensions. Freshly isolated rat cardiomyocytes were incubated with 1 or 10 mM isoproterenol and 20 microM Cu2+ for 4 h. The formation of an isoproterenol oxidation radical was detected in the extracellular medium, cells, membranes, and heavy organelles by electron spin resonance spectroscopy. An electron spin resonance signal assigned to leucoisoprenochrome-o-semiquinone increased in a time-dependent manner in the extracellular medium. A second electron spin resonance signal, characteristic of an immobilized radical, was also found in the cardiomyocytes. The latter was attributed to leucoisoprenochrome-o-semiquinone immobilized on cellular components such as membranes, cytoskeleton, nucleus, and heavy organelles. In addition, the levels of leucoisoprenochrome-o-semiquinone decreased in the presence of glutathione. Computer simulations of the experimental spectra indicate the formation of two distinct isomeric leucoisoprenochrome-o-semiquinone radicals during isoproterenol oxidation. The present study shows that the isoproterenol oxidation in isolated rat cardiomyocytes correlates with the formation of leucoisoprenochrome-o-semiquinone in the cells and in the extracellular medium, suggesting that it might be involved in cardiotoxicity induced by the oxidation of catecholamines.     

Is inhibition of cancer angiogenesis and growth by paclitaxel schedule dependent?

It has been speculated that weekly paclitaxel enhances antiangiogenesis and, hence, results in a greater inhibition of cancer growth than the 3-week schedule. We compared the weekly and 3-week schedules of paclitaxel in inhibiting angiogenesis, tumor growth and bone marrow hematopoiesis in a lung cancer model. Vehicle or paclitaxel was administered i.p. to three groups of nude mice bearing a human lung cancer. The vehicle was given weekly for six doses or every 3 weeks for two doses (Group A). Paclitaxel was administered at 20 mg/kg/week for six doses (Group B) or 60 mg/kg/3 weeks for two doses (Group C). The tumor growth rate was reduced by 50% equally in both the paclitaxel-treated groups. Intratumoral microvasculature was reduced by 70% in each paclitaxel-treated group. However, white blood cell count was significantly reduced in Group C in comparison with that of Group A or B. We conclude that in this model, angiogenesis and tumor growth were inhibited to the same extent when paclitaxel was administered on a weekly or 3-week schedule. Inhibition of tumor growth by paclitaxel was associated with suppression of angiogenesis. Weekly administration of paclitaxel resulted in a lower degree of leukopenia than with the 3-week schedule, mimicking the clinical setting.