Strategies for reduction of anthracycline cardiac toxicity

The term 'periventricular leukomalacia' (PVL) usually covers necrotic and/or gliotic lesions from perinatal origin occurring in the periventricular ring of telencephalic white matter. PVLs are found post-mortem in one third of brains from autopsies of premature infants; PVLs are diagnosed in 4 to 10% of infants born before 33 weeks of gestation and remaining alive more than 3 days after birth. PVL is very rare in at term infants. The proportion of PVLs from prenatal origin is estimated between one third and one half of cases. Recent progresses in neuroepidemiology, developmental neurobiology and imaging methods permit to revisit the pathophysiology of PVLs on a multifactorial basis. The final result of these multiple factors seem to be calcium influx due to glutamatergic overactivation triggered by cytokines, infection and inflammation, and deficit in neurotrophic factors. Periventricular topography can be explained by properties of intracerebral vascular wall at this stage of angiogenesis and by perfusion failure/hypoxia.     

Clinical cardiotoxicity following anthracycline treatment for childhood cancer: the Pediatric Oncology Group experience

PURPOSE: To determine the incidence of clinical cardiotoxicity from anthracycline chemotherapy in children with cancer and to identify associated risk factors. PATIENTS AND METHODS: The study population consisted of 6,493 children with cancer who had received anthracycline chemotherapy on Pediatric Oncology Group (POG) protocols from 1974 to 1990. Cardiotoxicity, defined as congestive heart failure not due to other causes, abnormal measurements of cardiac function that prompted discontinuation of therapy, or sudden death from presumed cardiac causes, was determined by a review of protocol records. RESULTS: Cardiotoxicity was confirmed in 106 patients (1.6%): 58 had congestive heart failure, 43 had changes in measures of cardiac function that prompted the discontinuation of therapy, and five died suddenly from presumed cardiac causes. In a multivariate analysis, factors that contributed to the relative risk (RR) of toxicity were a cumulative anthracycline dose > or = 550 mg/m2 of body-surface area (RR = 5.2), maximal dose > or = 50 mg/m2 (RR = 2.8), female sex (RR = 1.9), black race (RR = 1.7), presence of trisomy 21 (RR = 3.4), and exposure to amsacrine (RR = 2.6). Cardiotoxicity within 1 year after the completion of anthracycline treatment (early cardiotoxicity) represented 89.5% of all cases. CONCLUSION: Early clinical cardiotoxicity in children treated with anthracycline is rare. A high maximal dose, or cumulative dose of anthracycline, female sex, black race, presence of trisomy 21, and treatment with amsacrine increase the risk for anthracycline-associated cardiotoxicity.     

Strategies for prevention of infection in short-duration neutropenia

Although infection continues to be a major cause of morbidity and mortality in neutropenic patients, newer strategies have resulted in a shorter duration of neutropenia. The prime risk to patients with short-duration neutropenia (defined as neutropenia of less than 14 days) is bacterial infection, which is reduced by the administration of prophylactic antibiotics, and possibly by the use of clean food, sterile water, and protection against transmission of organisms from healthcare workers' hands.     

Strategies for the prevention of maladaptive fear responses.

Discusses the relevance of experimental approaches to primary prevention of some behavior disorders in the context of immunological concepts. Three models of prevention drawn from the behavioral literature are presented, including the authors' research findings on preexposure and observational learning in 33 1st graders. All methods tested proved capable of attenuating Ss' subsequent response to noxious stimuli. Recommendations for further research on the clinical application of these experimental models are offered. (French summary) (2 p ref) (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Strategies for implementing a media-based AIDS prevention program.

We describe a media-based acquired immune deficiency syndrome (AIDS)-prevention program involving print and TV media. For 6 consecutive days, 5- to 10-min segments addressing AIDS and the family were televised on the noon and 9 p.m. news broadcasts of a major local TV station in the Midwest. On the 1st day of the broadcast, more than 1 million educational supplements were distributed to the general public through a local newspaper. This manual provided viewers a more in-depth coverage of the issues presented on the TV broadcasts. Issues involved in the funding and creation of this program are discussed. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Strategies for the prevention of cytomegalovirus disease after marrow transplantation

The purposes of this review are to examine the epidemiology of disease due to cytomegalovirus (CMV) in recipients of autologous and allogeneic marrow transplants and to compare different antiviral regimens used for the prevention of such disease in recipients of allogeneic marrow transplants, with an emphasis on ganciclovir. In seven studies, ganciclovir reduced the incidence of CMV infection and disease after allogeneic marrow transplantation. In one study mortality after transplantation was reduced because of a decreased rate of CMV-related death among ganciclovir-treated patients. Ganciclovir was effective when given to all CMV-seropositive patients (prophylaxis) or to patients who were considered at high risk for CMV disease on the basis of a positive surveillance culture (early treatment). The effectiveness of ganciclovir for the prevention of CMV infection and disease is limited by drug-induced neutropenia. Experience with other antiviral agents, such as foscarnet, has been limited. Initial studies of the adoptive transfer of CMV-specific CD8+ cytotoxic T cells have been conducted. In short, ganciclovir is currently effective for the prevention of CMV disease in allogeneic marrow transplant recipients, but its usefulness is limited by neutropenia. Future studies must be aimed at confining the toxicity of ganciclovir to patients at the highest risk for CMV disease.     

Role of iron in the potentiation of anthracycline cardiotoxicity: identification of heart cell mitochondria as a major site of iron-anthracycline interaction

The effect of nitric oxide on the lipopolysaccharide (LPS)-induced cytokine production by alveolar macrophages was studied. When alveolar macrophages were cultured, substantial amounts of interleukin-1(IL-1), interleukin-6 (IL-6), tumor necrosis factor alpha(TNF-alpha), and nitric oxide are produced upon stimulation with LPS. Inhibition of the nitric oxide production by the L-arginine analogue N(G)-monomethyl-L-arginine (NMMA), resulted in an increase of IL-1(beta) and IL-6, whereas the TNF-alpha concentrations remained unchanged, suggesting specific inhibitory effects of nitric oxide on the LPS-stimulated cytokine production by alveolar macrophages. The observed cytokine-modulation properties of nitric oxide did not result from cytotoxic actions of the oxidation of L-arginine on macrophages, since nitric oxide synthesis did not affect the viability of the alveolar macrophages. Conversely the nitric oxide donor S-nitroso-N-acetyl-D, L-penicillamine (SNAP) induced dose-dependent inhibition of IL-1 production in LPS-stimulated alveolar macrophages in which endogenous nitric oxide production was blocked. The results indicate that nitric oxide can affect the LPS-induced IL-1beta and IL-6 secretion by alveolar macrophages in an autoregulatory way and are discussed in view of the important physiologic consequences this autoregulation by nitric acid oxide may have.     

Strategies for the prevention of a successful biological warfare aerosol attack

We evaluated the usefulness of dynamic turbo FLASH MR imaging in the differential diagnosis of complications after renal transplantation in 17 patients (10 from living relatives and 7 from cadavers). Coronal turbo FLASH dynamic images were obtained every 5 sec for 5 min after an intravenous bolus injection of Gd-DTPA. Corticomedullary differentiation (CMD) on spin echo coronal T1-weighted images and MR renogram patterns of the renal cortex and medulla were obtained for quantitative analysis of the Gd-DTPA-enhanced dynamic turbo-FLASH images. The signal intensity ratio of the medulla to cortex after Gd-DTPA enhancement was compared among four groups: normal (n = 9), acute tubular necrosis (ATN) or cyclosporine A (CyA) tubulopathy (n = 6), acute rejection (AR) in the living related donor kidney (n = 4), and AR in the cadaveric kidney (n = 5). Although loss of CMD was seen in severe renal dysfunction in the transplanted kidneys, there was considerable overlap among the four groups. On dynamic study, there was significant differences in the signal intensity ratio of the medulla to cortex between normally functioning kidneys or ATN/CyA tubulopathy and AR (p < 0.01). In patients with severe renal dysfunction, the arterial cortical peak was indistinct. In conclusion, MR renograms obtained from dynamic turbo FLASH MR imaging played a significant role in evaluating dysfunction of the renal transplant.     

Strategies for the prevention of iron deficiency through foods in the household

Iron deficiency can be caused not only by diets deficient in iron but by poor absorption of available dietary iron. Extrinsically tagging foods with radioiron allows the exact measurement of iron absorbed from heme and nonheme iron foods. It has furthered the study of the effect of enhancers and inhibitors of iron absorption. As a result, we have a greater understanding of why iron deficiency and iron deficiency anemia are prevalent in populations of low socioeconomic status and of which food vehicles and iron compounds are most suitable for iron fortification.     

Cyclophosphamide cardiotoxicity

A 12-year-old boy with aplastic anemia developed severe but reversible cardiac failure after treatment with 200 mg/kg cyclophosphamide (4 x 50 mg/kg on four consecutive days) given as preparation for bone marrow grafting. This and previously reported cases demonstrate the possibility of cardiotoxicity after high doses of the drug.     

Strategies for modifying sexual behavior for primary and secondary prevention of HIV disease.

Sexual behavior change is needed for both the primary and secondary prevention of HIV disease. Remarkable progress has been made in modifying high-risk behaviors in selected populations (e.g., gay men living in the epicenters of the epidemic). However, many at-risk populations (e.g., gay men living outside these epicenters, homosexual men who are young or Black, ethnic minorities—especially women of childbearing age, and persons over age 50) have received relatively little research attention and may be at risk for further infection. A community-level approach to behavior change represents one kind of comprehensive strategy to achieve significant reduction in the spread of HIV. Effective approaches at this level require component interventions that are effective in changing behavior and acceptable to target populations. Also needed is an infrastructure to support behavioral change efforts. Lacking at present is a comprehensive and coordinated structure to conceptualize, stimulate, and support the continuum of behavioral research needed for the control of HIV and other sexually transmitted diseases. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Ventricular repolarization time indexes following anthracycline treatment

The anthracyclines, doxorubicin and daunorubicin, are antibiotics effective in the treatment of many malignancies. However, their usefulness is limited by the development of potentially fatal cardiotoxicity. Cardiac monitoring by a noninvasive test capable of identifying patients at high risk of cardiac damage, before the ejection fraction deteriorates would have clinical utility. Electrocardiograms and echocardiograms are routinely utilized for noninvasive assessment of myocardial function. However, of the ECG abnormalities described, none has been noted to be of consistent predictive value for cardiotoxicity. The aim of this study was to assess the effects of doxorubicin on ventricular repolarization time indexes, as they have been shown to be effective in the identification of electrical myocardial instability and, hence, in the identification of risk for either arrhythmia or heart failure. For this reason, electrocardiograms were compared in 35 cancer patients at the first presentation (drug-free state) and after 29.4 +/- 37.65 weeks of treatment with doxorubicin. The results of the present study showed that after only a short period of treatment with doxorubicin there was a significant increase in ventricular recovery time dispersion indexes (QTc, JT, and JTc dispersion, and their "adjusted" values). Thus, increased regional variation in ventricular repolarization could be, in the absence of a significant modification of the echocardiographic parameters, an early marker of an electropathy, due to the early cardiotoxic action of doxorubicin on myocardial cells, eventually leading to heart failure.     

Biosynthesis of anthracycline antibiotics by Streptomyces galilaeus. II. Structure of new anthracycline antibiotics obtained by microbial glycosidation and biological activity

New anthracycline antibiotics derived from epsilon-, gamma- and beta-rhodomycinones and epsilon-isorhodomycinone by the microbial glycosidation using an aclacinomycin-negative mutant, the strain KE303, of Streptomyces galilaeus MA144-M1 were studied to elucidate their structures and biological activities. These antibiotics were the products in which the anthracyclinones added as precursors were linked at C-7 or C-10 position with the same trisaccharide moiety (cinerulosyl-2-deoxyfucosyl-rhodosaminyl group) as in the parental antibiotic aclacinomycin A. In addition to antimicrobial activity, they exhibited the growth inhibition of cultured L1210 leukemia cells and the marked inhibition against DNA and RNA synthesis.     

Ultratight DNA binding of a new bisintercalating anthracycline antibiotic

Differential scanning calorimetry and absorption spectroscopy were used to characterize the interaction of the new bisintercalating anthracycline antibiotic, WP631, with DNA. The method of continuous variations revealed five distinct binding modes for WP631, corresponding to 6, 3, 1.3, 0.5, and 0.25 mol of base pairs (bp) per mole of ligand. The binding of one drug to 6 bp corresponds to the bisintercalative binding mode determined previously, and was the mode studied in detail. UV melting experiments and differential scanning calorimetry were used to measure the ultratight binding of WP631 to DNA. The binding constant for the interaction of WP631 with herring sperm DNA was determined to be 3.1 (+/- 0.2) x 10(11) M-1 at 20 degrees C. The large, favorable binding free energy of -15.3 kcal mol-1 was found to result from a large, negative enthalpic contribution of -30.2 kcal mol-1. DNA melting curves at different concentrations of WP631 were fitted to McGhee's model of DNA melting in the presence of ligands, yielding an independent estimate of DNA binding parameters. The salt dependence of the WP631 binding constant was examined, yielding a slope SK = delta (log K)/delta (log[Na+]) = 1.63. The observed salt dependence of the equilibrium constant, interpreted according to polyelectrolyte theory, indicates that there is a significant nonpolyelectrolyte contribution to the binding free energy. DNA melting studies using a homogeneous 214 bp DNA fragment showed that WP631 binds preferentially to the GC-rich region of the DNA.