Left Ventricular Systolic Dysfunction and Cardiovascular Outcomes in Tetralogy of Fallot: Systematic Review and Meta-analysis

BackgroundAlthough there are robust data about the pathophysiology and prognostic implications of left ventricular (LV) systolic dysfunction in patients with acquired heart disease, similar prognostic data about LV systolic dysfunction are sparse in the tetralogy of Fallot (TOF) population. The purpose of this study was to perform a meta-analysis of all studies that assessed the relationship between LV ejection fraction (LVEF) and cardiovascular adverse events (CAEs) defined as death, aborted sudden death, or sustained ventricular tachycardia.MethodsWe used random-effects models to calculate hazard ratios (HRs) and 95% confidence intervals (CIs).ResultsOf the 1,809 citations, 7 studies with 2,854 patients (age 28 ± 4 years) were included. During 5.6 ± 3.4 years' follow-up, there were 82 deaths, 17 aborted sudden cardiac deaths, and 56 sustained ventricular tachycardia events. Overall, CAEs occurred in 5.1% (144 patients). As a continuous variable, LVEF was a predictor of CAE (HR 1.29, 95% CI, 1.09-1.53, P = 0.001) per 5% decrease in LVEF. Similarly, LVEF < 40% was also a predictor of CAE (HR 3.22, 95% CI, 2.16-4.80, P < 0.001).ConclusionsLV systolic dysfunction was an independent predictor of CAE, and we observed a 30% increase in the risk of CAE for every 5% decrease in LVEF, and a 3-fold increase in the risk of CAE in patients with LVEF <40% compared with other patients. These findings underscore the importance of incorporating LV systolic function in clinical risk stratification of patients with TOF and the need to explore new treatment options to address this problem.     

IgAs against acetaldehyde-modified red cell protein as a marker of ethanol consumption in male alcoholic subjects, moderate drinkers, and abstainers

BACKGROUND: Alcohol abuse has been shown to result in the production of antibodies against acetaldehyde-modified epitopes in proteins. However, as yet, only limited information has been available on the clinical usefulness of such responses as markers of hazardous drinking. METHODS: We developed an ELISA to measure specific IgAs against acetaldehyde-protein adducts. This method was evaluated in cross-sectional and follow-up studies on male heavy drinkers with a current ethanol consumption of 40 to 540 g/d (n=40), moderate drinkers consuming 1 to 40 g/d (n=25), and abstainers (n=16). The clinical assessments included detailed interviews on the amounts and patterns of ethanol consumption and various biochemical markers of alcohol abuse and liver function. RESULTS: The mean antiadduct IgAs (198+/-28 U/L) in the alcohol abusers were significantly higher than those in the moderate drinkers (58+/-11 U/L, p<0.001) or abstainers (28+/-8 U/L, p<0.001). The values of moderate drinkers were also higher than those in abstainers (p<0.05). The amount of ethanol consumed during the period of 1 month preceding blood sampling correlated strongly with antiadduct IgAs (r=0.67, p<0.001). The sensitivity (73%) and specificity (94%) of this marker were found to exceed those of the conventional laboratory markers of alcohol abuse in comparisons contrasting heavy drinkers with abstainers although not in comparisons contrasting heavy drinkers with moderate drinkers. During abstinence, antiadduct IgAs disappeared with a mean rate of 3% per day. In additional analyses of possible marker combinations, antiadduct IgAs, together with CDT, were found to provide the highest sensitivity and specificity. CONCLUSIONS: Measurements of antiadduct IgAs may provide a new clinically useful marker of alcohol abuse, providing a close relationship between marker levels and the actual amounts of recent ethanol ingestion.     

Intraoperative electron and external beam irradiation with or without 5-fluorouracil and maximum surgical resection for previously unirradiated,locally recurrent colorectal cancer

PURPOSE/OBJECTIVE: 1) Disease control and survival will be evaluated for treatment regimens containing intraoperative electron irradiation (IOERT) for locally recurrent, previously unirradiated colorectal cancers. 2) Various prognostic factors will be evaluated to determine whether they have an impact on disease control or survival. MATERIALS AND METHODS: From April 1981 through August 1995, 123 patients with previously unirradiated locally recurrent colorectal cancers received IOERT at our institution, usually as a supplement to external beam irradiation (EBRT) and maximum resection. All received EBRT with or without concomitant 5-fluorouracil-based chemotherapy. Forty-five Gy in 25 fractions was given to the tumor or tumor bed plus 3-cm to 5-cm margins in 121 of 123 patients and a boost of 5.4 to 9 Gy in 3 to 5 fractions to the tumor plus 2-cm margins. Maximum resection was performed before or after EBRT. IOERT doses ranged from 10 to 20 Gy in 119 of 123 patients, with dose dependent on resection margins (130 fields in 123 patients). Maintenance chemotherapy was given to only two patients. RESULTS: Disease relapse and survival were evaluated. Central failure (within the IOERT field) was documented in 13 of 123 patients (11 percent) with a five-year actuarial rate of 26 percent. Local relapse (in EBRT field) occurred in 24 patients (20 percent); five-year rate was 37 percent. Distant metastases occurred in 66 patients (54 percent); five-year rate was 72 percent. Median survival was 28 months, with overall survival at two, three, and five years of 62, 39, and 20 percent, respectively. Tolerance data suggest a relationship between IOERT dose and incidence of Grade 2 or 3 neuropathy (12.5 Gy, 2 of 29 or 7 percent; 15 Gy, 19 of 101 or 19 percent;P=0.12). Survival and disease control were analyzed as a function of potential prognostic factors. None of the prognostic factors had a significant impact on disease control or survival. Although there was a trend for reduction in local relapse rates with gross totalvs. partial resection, this neither achieved statistical significance nor translated into improved survival. Patients with gross residual disease after maximum resection had three-year and five-year survival rates of 36 and 18 percent, respectively, which paralleled results for patients with gross total resection at 41 and 24 percent, respectively. CONCLUSION: Encouraging trends for improved local control with or without survival exist in separate locally recurrent colorectal IOERT analyses from our institution and other institutions. Therefore, continued evaluation of IOERT approaches seems warranted. Disease control within the IOERT and external fields is decreased when the surgeon is unable to accomplish a gross total resection. Therefore, it is reasonable to consistently add 5-fluorouracil or other dose modifiers during EBRT and to evaluate the use of dose modifiers in conjunction with IOERT (sensitizers and hyperthermia). In view of high systemic failure rates of >50 percent in patients with locally recurrent disease, more routine use of systemic therapy is indicated as a component of IOERT-containing treatment regimens (use existent chemotherapy and/or develop effective immunotherapy and gene transfer therapy). Even with locally recurrent lesions, the aggressive multimodality approaches including IOERT have resulted in improved local control and long-term survival rates of 20 percentvs. an expected 5 percent with conventional techniques.Supported in part by Mayo Comprehensive Cancer Grant CA 15083-18A1A2.Poster presentation at the meeting of the American Society of Therapeutic Radiology and Oncology, Miami Beach, Florida, October 28 to November 1, 1995.     

Uptake and presentation of hepatitis C virus-like particles by human dendritic cells

Hepatitis C virus (HCV) is a major cause of chronic hepatitis worldwide. Interaction of dendritic cells (DCs) with viral particles may play an important role in the immunopathogenesis of HCV infection. Since the synthesis or purification of infectious virions is limited, we used HCV-like particles (HCV-LPs) to study the interaction of HCV with human DCs. Immature DCs exhibited an envelope-specific and saturable binding of HCV-LPs, indicating receptor-mediated DC-HCV-LP interaction. Confocal microscopy revealed that HCV-LPs were rapidly taken up by DCs in a temperature-dependent manner. Competition experiments demonstrated that C-type lectins such as mannose receptor or DC-SIGN (DC-specific intercellular adhesion molecule 3-grabbing nonintegrin) were not sufficient for mediating HCV-LP binding. HCV-LP uptake was followed by DC activation. DCs pulsed with HCV-LPs stimulated HCV core-specific CD4(+) T cells, indicating that uptake of HCV-LPs by DCs leads to antigen processing and presentation on major histocompatibility complex (MHC) class II molecules. Finally, HCV-LP-derived antigens were efficiently cross-presented to HCV core-specific CD8(+) T cells. These findings demonstrate that HCV-LPs represent a novel model system to study HCV-DC interaction allowing definition of the molecular mechanisms of HCV uptake, DC activation, and antigen presentation to T cells. Furthermore, HCV-LP-mediated DC activation and efficient antigen presentation may explain the marked immunogenicity of HCV-LPs in vivo.     

Atresia of the coronary sinus in patients with supraventricular tachycardia

Background: Atresia of the coronary sinus (CS) ostium with retrograde drainage of the cardiac veins via the persistent left superior vena cava (PLSVC) is a rare abnormality and only a few case reports in association with electrophysiological studies have been reported.
Methods: During standard electrophysiological study in three patients with a focal left atrial tachycardia, atrial fibrillation and common type right atrial flutter, the CS could not be cannulated despite several attempts. Assuming an occluded CS ostium we advanced a multipurpose catheter via the right atrium and the right superior vena cava in a PLSVC and performed CS angiography.
Results: CS angiography showed that the CS was occluded in all 3 patients and the PLSVC was used as a drainage route to the superior vena cava. After retrograde placement of a 2.5 Fr nonsteerable diagnostic catheter via the PLSVC in the CS, the intracardiac CS electrogram was recorded. Successful ablation could be performed in all three cases.
Conclusions: The cases highlight the possibility that failure to access the CS during electrophysiological studies may be related to this anomaly and that retrograde cannulation via PLSVC enables the CS access and acquisition of its electrograms.     

Allergy to 3-nitro-p-hydroxyethylaminophenol and 4-amino-3-nitrophenol in a hair dye

Contact allergy to 3‐nitro‐p‐hydroxyethylaminophenol in a hair dye is described for the first time. p‐Phenylenediamine is the most common screening allergen when allergic contact dermatitis is suspected, but sometimes the allergen is not sufficient for diagnosing allergic contact dermatitis to hair dyes. A 50‐year‐old woman developed a severe scalp dermatitis and developed vesicular hand eczema for the first time in her life. Patch testing was performed with the European Standard Series. The patch testing was supplemented with a local series of cosmetic allergens and the hairdresser's series. At the initial patch testing, there was a + reaction to nickel and a +? to PPD at days 3 and 7. Further, she reacted with a +? to her own hair collected at day 3 after the hair dying which elicited the dermatitis reaction. Open exposure to the product, which had initiated the dermatitis, was negative both before and after the allergic reaction to the product. None of the screening chemicals in the hairdresser's series gave a definite positive reaction. Only by patch testing with the individual hair dye product ingredients, the patient's reactions were explained. The patient gave a positive patch test to 4‐amino‐3‐nitrophenol and 3‐nitro‐p‐hydroxyethylaminophenol at days 3–4 reading.     

Designing immunotoxins for cancer therapy

Immunotoxins are the rapeutic agents with a high degree of specificity and unique mechanism of action. An immunotoxin is achimeric protein consisting of a targeting moiety linked to a toxin. The targeting moiety selectively binds to a tumor cell and targets it for death via the attached toxin. Generally, immunotoxins are specifically potent against cancer cells in vitro and in animal models of human malignancies. However, immunotoxins can be limited clinically by immunogenicity, toxicity, and instability. In this review, weofferwaysto overcome these limitations to create “ideal immunotoxins” for cancer therapy. These include producing single chain targeting/toxin fusion proteins of fully human origin that are extracellularly stable but once internalized, can be cleaved by intracellular proteases to free the toxin and facilitate its translocation to the cytosol.