Managing Drug Interactions With Oral Anticancer Treatments.

The use of oral anticancer treatments is widespread and vital to modern cancer treatment. Novel oral chemotherapy and targeted therapy treatments continue to receive US Food and Drug Administration approval every year, making knowledge of these agents a necessity for practitioners working in oncology. Many oral anticancer agents are prone to drug interactions that can contribute to adverse effects and decrease therapy efficacy. Potential drug-drug interactions include (1) interactions with CYP3A4 inhibitors and inducers, (2) interactions related to gastric acid suppression, (3) interactions related to prolongation of the cardiac QT interval, (4) interactions related to anticoagulant medications, and (5) drug-food and drug-herb interactions. Identifying potential drug interactions and appropriately managing them is key to preventing adverse effects and ensuring maximum efficacy while on oral anticancer therapy. Management of adverse effects increases patient compliance, ensures medication safety, and allows patients to remain on therapy. This article discusses the mechanisms of interactions and types of interacting medications. Specific recommendations are discussed.

Remote sensing tree classification with a multilayer perceptron.

To accelerate scientific progress on remote tree classification-as well as biodiversity and ecology sampling-The National Institute of Science and Technology created a community-based competition where scientists were invited to contribute informatics methods for classifying tree species and genus using crown-level images of trees. We classified tree species and genus at the pixel level using hyperspectral and LiDAR observations. We compared three algorithms that have been implemented extensively across a broad range of research applications: support vector machines, random forests, and multilayer perceptron. At the pixel level, the multilayer perceptron algorithm classified species or genus with high accuracy (92.7% and 95.9%, respectively) on the training data and performed better than the other two algorithms (85.8-93.5%). This indicates promise for the use of the multilayer perceptron (MLP) algorithm for tree-species classification based on hyperspectral and LiDAR observations and coincides with a growing body of research in which neural network-based algorithms outperform other types of classification algorithm for machine vision. To aggregate patterns across the images, we used an ensemble approach that averages the pixel-level outputs of the MLP algorithm to classify species at the crown level. The average accuracy of these classifications on the test set was 68.8% for the nine species.

The efficacy of GlideScope® videolaryngoscopy compared with direct laryngoscopy in children who are difficult to intubate: an analysis from the paediatric difficult intubation registry.

BACKGROUND: We analysed data from the Paediatric Difficult Intubation Registry examining the use of direct laryngoscopy and GlideScope® videolaryngoscopy. METHODS: Data collected by a multicentre, paediatric difficult intubation registry from 1295 patients were analysed. Rates of success and complications between direct laryngoscopy and GlideScope videolaryngoscopy were analysed. RESULTS: Initial (464/877 = 53% vs 33/828 = 4%, Z-test = 22.2, P < 0.001) and eventual (720/877 = 82% vs. 174/828 = 21%, Z-test = 25.2, P < 0.001) success rates for GlideScope were significantly higher than direct laryngoscopy. Children weighing <10 kg had lower success rates with the GlideScope than the group as a whole. There were no differences in complication rates per attempt between direct laryngoscopy and GlideScope. The direct laryngoscopy group had more complications associated with the greater number of attempts needed to intubate. There were no increased risks of hypoxia or trauma with GlideScope use. Each additional attempt at intubation with either device resulted in a two-fold increase in complications (odds ratio: 2.0, 95% confidence interval: 1.5-2.5, P < 0.001). CONCLUSIONS: During difficult tracheal intubation in children, direct laryngoscopy is an overly used technique with a low chance of success. GlideScope use was associated with a higher chance of success with no increased risk of complications. GlideScope use in children with difficult tracheal intubation has a lower success rate than in adults with difficult tracheal intubation. Children weighing less than 10 kilograms had lower success rates with either device. Attempts should be minimized with either device to decrease complications.

The effects of obesity and type 2 diabetes mellitus on cardiac structure and function in adolescents and young adults.

AIMS/HYPOTHESIS: We sought to evaluate the effects of obesity and obesity-related type 2 diabetes mellitus on cardiac geometry (remodelling) and systolic and diastolic function in adolescents and young adults. METHODS: Cardiac structure and function were compared by echocardiography in participants who were lean, obese or obese with type 2 diabetes (obese diabetic), in a cross sectional study. Group differences were assessed using ANOVA. Independent determinants of cardiac outcome measures were evaluated with general linear models. RESULTS: Adolescents with obesity and obesity-related type 2 diabetes were found to have abnormal cardiac geometry compared with lean controls (16% and 20% vs <1%, p < 0.05). These two groups also had increased systolic function. Diastolic function decreased from the lean to obese to obese diabetic groups with the lowest diastolic function observed in the obese diabetic group (p < 0.05). Regression analysis showed that group, BMI z score (BMIz), group × BMIz interaction and systolic BP z score (BPz) were significant determinants of cardiac structure, while group, BMIz, systolic BPz, age and fasting glucose were significant determinants of the diastolic function (all p < 0.05). CONCLUSIONS/INTERPRETATION: Adolescents with obesity and obesity-related type 2 diabetes demonstrate changes in cardiac geometry consistent with cardiac remodelling. These two groups also demonstrate decreased diastolic function compared with lean controls, with the greatest decrease observed in those with type 2 diabetes. Adults with diastolic dysfunction are known to be at increased risk of progressing to heart failure. Therefore, our findings suggest that adolescents with obesity-related type 2 diabetes may be at increased risk of progressing to early heart failure compared with their obese and lean counterparts.

Dobutamine stress echocardiography in the evaluation of young patients with Kawasaki disease.

There has been no consistent approach to the follow-up of Kawasaki disease patients for remote coronary perfusion abnormalities. Dobutamine stress echocardiography (DSE) has become a standard method for evaluation of perfusion abnormalities in adults with coronary artery disease. In addition, DSE has been used with success in some pediatric patients. The purposes of this study were to evaluate safety and accuracy of DSE in the follow-up of patients with Kawasaki disease, to evaluate whether DSE adds any additional value to the resting echocardiogram, and to determine the association of DSE results with American Heart Association (AHA) risk level categories. DSE was performed 1 month to 13 years after acute Kawasaki disease in 47 patients (range, 3.8-22.6 years; 33 males and 16 females). Patients were stratified according to AHA risk level categories (I-V). Ischemia was defined as a new or worsening regional wall motion abnormality or >1 mm ST segment depression on the electrocardiogram during DSE. In 45/47 patients, DSE was completed successfully (i.e., achievement of target heart rate or development of ischemia). No patients in risk levels lower than V (i.e., patients without coronary artery stenoses) had positive DSE, whereas 2/4 (50%) in the risk level V category had positive DSE, both of whom had coronary occlusion >50% confirmed by angiography. Of the 2 AHA risk level V patients with negative DSE, 1 had extensive collateralization and the other had coronary obstruction <50%. DSE is a safe and feasible method for the evaluation of children with Kawasaki disease. DSE provides a confirmatory benefit and may be a useful screening alternative to cardiac catheterization during follow-up. Patients in AHA risk levels I-IV are unlikely to have dobutamine-induced coronary perfusion abnormalities. Patients in the risk level V category may or may not have positive DSE depending on the degree of both coronary obstruction and collateralization.

Noncircumferential myofiber function: impact on early diastolic filling in children.

Circumferential and noncircumferential myofiber contraction may have varying impact on systolic and diastolic function. The purpose of this study was to determine the relation of circumferential, longitudinal, and oblique fiber shortening to early diastolic filling in children. Twenty-five patients (8.1 +/- 5.6 years of age; 12 boys and 13 girls) with normal echocardiograms and no heart disease had prospective echocardiographic evaluation of circumferential (shortening fraction, fractional area change), longitudinal (left ventricular axial shortening), combined circumferential and longitudinal (left ventricular ejection fraction), oblique (left ventricular systolic twist [LVST]) shortening, and early diastolic filling. Mean LVST was 16 +/- 8 degrees. There was no relation between early diastolic filling indexes and indexes of circumferential or longitudinal shortening. However, there was a significant inverse relation between heart rate-corrected E-wave acceleration time and LVST (r = 0.63, P <.001). Oblique fiber shortening affects early diastolic filling in children. Describing the functional role of noncircumferential left ventricular myofibers may improve our understanding of global left ventricular function.

Relation of heart rate to left ventricular dimensions in normotensive, normal-weight children, adolescents and adults.

BACKGROUND: The quantitative relation between body growth and changes in heart rate, and the relationship of heart rate to left ventricular (LV) dimensions, independent of the influence of body size, have been only marginally investigated. Accordingly, we designed this study to investigate the relation between heart rate, body size and LV dimensions in children, adolescents and adults over a broad age span. METHODS: Eight hundred and nineteen normotensive, multi-racial, normal-weight individuals (444 males, 375 females, aged 1-85 years) with normal LV systolic function were studied at echocardiography in three centers, using previously reported methods. The resting heart rate was measured on the M-mode echo-tracing or right after the echocardiogram with the subject still in the supine position. RESULTS: In children and adolescents (up to 17 years), the heart rate decreased with increasing body height (r = -0.51, p < 0.0001) and body weight (r = -0.42, p < 0.0001), in a similar manner in girls and boys. In adults, the heart rate was higher in women than in men, but it was not independently related to body size. The LV diastolic diameter was higher in males and decreased with increasing heart rate in children and adolescents (r = -0.45) as well as in adults (r = -0.25, both p < 0.0001). This relation was also independent of the effect of body size, sex and race. Similarly, the LV mass increased with decreasing heart rate in children and adolescents (r = -0.45), but the association was not confirmed after controlling for body size, sex and race. In adults, heart rate was inversely related to LV mass (r = -0.21, p < 0.0001), and this relation was also independent of body size, sex, race, age and blood pressure (p < 0.001). In women, the relation of heart rate to LV mass/height2.7 was less close than in men, due to the greater increase in LV mass with age. CONCLUSIONS: The heart rate has an inverse association with the LV chamber diameter and with the LV mass in children-adolescents and in adults. This relation is largely, but not uniquely, mediated by body proportions, especially during body growth.

Design and baseline characteristics for the ACE Inhibitor After Anthracycline (AAA) study of cardiac dysfunction in long-term pediatric cancer survivors.

PURPOSE: The ACE Inhibitor After Anthracycline (AAA) study is a randomized, double-blind, controlled clinical trial comparing enalapril with placebo to determine whether treatment can slow the progression of cardiac decline in patients who screen positive for anthracycline cardiotoxicity. METHODS: The primary outcome measure is the rate of decline, over time, in maximal cardiac index (in liters per minute per meters squared) at peak exercise; the secondary outcome measure is the rate of increase in left ventricular end systolic wall stress (in grams per centimeters squared). Patients >2 years off therapy and <4 years from diagnosis, aged 8 years and older, were eligible if they had received anthracyclines and had at least one cardiac abnormality identified at any time after anthracycline exposure. RESULTS: A total of 135 patients were randomized to enalapril or placebo. Baseline characteristics were similar across treatment groups. CONCLUSIONS: The AAA study will provide important information concerning the efficacy of using angiotensin-converting enzyme inhibitors to offset the effects of late anthracycline cardiotoxicity.

Postmodernism in marriage and family therapy training: doctoral students' understanding and experiences.

The purpose of this study is to advance our understanding of how doctoral students perceive postmodernism's influence in the field of Marriage and Family Therapy (MFT). According to the literature, postmodernism has had a profound impact on many fields, including MFT. However, tracking of how postmodernism is actually being rendered in theory, research, practice, and training warrants investigation. This study utilized focus group interviews to investigate the perceptions of MFT doctoral students. Findings suggest that while participants are attracted to postmodern tenets, they also report feeling a mixture of liberation and excitement with confusion and fear regarding how postmodernism is influencing MFT models of therapy.

Temporally regulated and tissue-specific gene manipulations in the adult and embryonic heart using a tamoxifen-inducible Cre protein.

The advent of conditional and tissue-specific recombination systems in gene-targeted or transgenic mice has permitted an assessment of single gene function in a temporally regulated and cell-specific manner. Here we generated transgenic mice expressing a tamoxifen-inducible Cre recombinase protein fused to two mutant estrogen-receptor ligand-binding domains (MerCreMer) under the control of the alpha-myosin heavy chain promoter. These transgenic mice were crossed with the ROSA26 lacZ-flox-targeted mice to examine Cre recombinase activity and the fidelity of the system. The data demonstrate essentially no Cre-mediated recombination in the embryonic, neonatal, or adult heart in the absence of inducing agent but >80% recombination after only four tamoxifen injections. Expression of the MerCreMer fusion protein within the adult heart did not affect cardiac performance, cellular architecture, or expression of hypertrophic marker genes, demonstrating that the transgene-encoded protein is relatively innocuous. In summary, MerCreMer transgenic mice represent a tool for temporally regulated inactivation of any loxP-targeted gene within the developing and adult heart or for specifically directing recombination and expression of a loxP-inactivated cardiac transgene in the heart.

Changes in left ventricular mass index in children and adolescents after renal transplantation.

Recent reports indicate a high prevalence of left ventricular hypertrophy (LVH) in children on dialysis and after renal transplantation (Tx), as identified by cross-sectional analysis. However, the evolution of LVH in pediatric patients with end-stage renal disease after renal Tx is not well established. To assess changes of left ventricular mass (LVM), we prospectively performed echocardiography in 23 children and adolescents between November 1998 and July 2000. Each patient had an echocardiographic evaluation while on dialysis (for at least 6 weeks) and a follow-up evaluation at least 6 months after successful renal Tx (i.e. with a measured glomerular filtration rate [GFR] of at least 40 mL/min/1.73 m2). The LVM index was estimated by indexing LVM to height(2.7). Sixteen patients had a cadaveric transplant and seven had a live donor transplant; the mean duration between the two studies was 1.9 +/- 1.6 yr; and the mean GFR was 55.0 +/- 21.4 mL/min/1.73 m2. There was no significant difference in the mean values of the LVM index while on dialysis and after renal Tx (43.9 +/- 17.8 g/m2.7 and 39.3 +/- 12.0 g/m2.7, respectively, p = 0.19), or in the prevalence of LVH (52% and 56%, respectively). Interval changes in the LVM index in individual subjects between the two studies were significantly associated with interval changes in indexed systolic (r = 0.42, p = 0.04) and diastolic (r = 0.42, p = 0.05) blood pressures. Interval changes in hemoglobin, blood urea nitrogen (BUN), creatinine, and duration after Tx did not correlate with changes in the LVM index. There was no significant difference in LVM index change according to the type of dialysis, donor source, and the cause of renal failure. In multivariate analysis, the baseline LVM index and changes in indexed SBP were independent predictors for LVM index change after renal Tx. We conclude that LVH persists in children and adolescents after renal Tx. Control of blood pressure might be an important factor in regression or prevention of progression of LVH in these patients.

The transcription factors GATA4 and GATA6 regulate cardiomyocyte hypertrophy in vitro and in vivo.

The zinc finger-containing transcription factors GATA4 and GATA6 are important regulators of basal and inducible gene expression in cardiac and smooth muscle cell types. Here we demonstrate a direct functional role for GATA4 and GATA6 as regulators of cardiomyocyte hypertrophic growth and gene expression. To model the increase in endogenous GATA4 and GATA6 transcriptional activity that occurs in response to hypertrophic stimulation, each factor was overexpressed in cardiomyocytes using recombinant adenovirus. Overexpression of either GATA4 or GATA6 was sufficient to induce cardiomyocyte hypertrophy characterized by enhanced sarcomeric organization, a greater than 2-fold increase in cell surface area, and a significant increase in total protein accumulation. In vivo, transgenic mice with 2.5-fold overexpression of GATA4 within the adult heart demonstrated a slowly progressing increase in heart to body weight ratio, histological features of cardiomyopathy, and activation of hypertrophy-associated genes, suggesting that GATA factors are sufficient regulators of cardiomyocyte hypertrophy in vitro and in vivo. To evaluate the requirement of GATA factors as downstream transcriptional mediators of hypertrophy, a dominant negative GATA4-engrailed repressor fusion-encoding adenovirus was generated. Expression of GATA4-engrailed blocked GATA4- and GATA6-directed transcriptional responses and agonist-induced cardiomyocyte hypertrophy, demonstrating that cardiac-expressed GATA factors are necessary mediators of this process.

Mouse model of desmin-related cardiomyopathy.

BACKGROUND: The consequence of upregulation of desmin in the heart is unknown. Mutations in desmin have been linked to desmin-related myopathy (DRM), which is characterized by abnormal intrasarcoplasmic accumulation of desmin, but direct causative evidence that a desmin mutation leads to aberrant intrasarcoplasmic desmin accumulation, aggregation, and cardiomyopathy is lacking. METHODS AND RESULTS: Multiple transgenic mouse lines that expressed either murine wild-type desmin or a 7-amino acid deletion (R173 through E179) desmin (D7-des) mutation linked to DRM were made. The distribution of desmin protein was unchanged, and no overt phenotype was detected in the wild-type desmin transgenic mice. In contrast, the D7-des mouse heart showed aberrant intrasarcoplasmic and electron-dense granular filamentous aggregates that were desmin-positive and characteristic of human DRM. The desmin filament network was significantly disrupted, and myofibril alignment was visibly compromised. Although systolic function at the whole-organ level was substantially conserved in the young adult animals, the ability of the heart to respond to beta-agonist stimulation, as measured in the intact animal, was significantly blunted. CONCLUSIONS: Upregulation of desmin protein at moderate levels is not detrimental. However, the D7-des mutation is dominant negative, and expression of the mutant protein leads to the appearance of aggregates that are characteristic of and diagnostic for human desmin-related cardiomyopathy.

Targeted inhibition of calcineurin attenuates cardiac hypertrophy in vivo.

The Ca(2+)-calmodulin-activated Ser/Thr protein phosphatase calcineurin and the downstream transcriptional effectors of calcineurin, nuclear factor of activated T cells, have been implicated in the hypertrophic response of the myocardium. Recently, the calcineurin inhibitory agents cyclosporine A and FK506 have been extensively used to evaluate the importance of this signaling pathway in rodent models of cardiac hypertrophy. However, pharmacologic approaches have rendered equivocal results necessitating more specific or genetic-based inhibitory strategies. In this regard, we have generated Tg mice expressing the calcineurin inhibitory domains of Cain/Cabin-1 and A-kinase anchoring protein 79 specifically in the heart. DeltaCain and DeltaA-kinase-anchoring protein Tg mice demonstrated reduced cardiac calcineurin activity and reduced hypertrophy in response to catecholamine infusion or pressure overload. In a second approach, adenoviral-mediated gene transfer of DeltaCain was performed in the adult rat myocardium to evaluate the effectiveness of an acute intervention and any potential species dependency. DeltaCain adenoviral gene transfer inhibited cardiac calcineurin activity and reduced hypertrophy in response to pressure overload without reducing aortic pressure. These results provide genetic evidence implicating calcineurin as an important mediator of the cardiac hypertrophic response in vivo.

Guidelines for cardiac sonographer education: recommendations of the American Society of Echocardiography Sonographer Training and Education Committee.

In 1992, the American Society of Echocardiography published a report of the Sonographer Education and Training Committee's recommendations for education of sonographers who perform echocardiographic procedures. Since the publication of the original document, there has been continual progress in technology with the development of more sophisticated diagnostic applications that allow more information to be obtained from echocardiographic procedures. These recent changes in the clinical application of echocardiography should be included in all cardiac sonographer education programs. The American Society of Echocardiography, a professional society that currently represents approximately 2500 cardiac sonographers, provides these updated guidelines.

Unique echocardiographic features associated with deployment of the Amplatzer atrial septal defect device.

The purpose of this study was to describe the unique echocardiographic findings associated with deployment of the Amplatzer atrial septal defect (ASD) device. Thirty-five patients (2 to 40 years old; 23 female and 12 male patients) underwent echocardiography during attempted ASD closure with the Amplatzer device. Transesophageal and transthoracic echocardiograms were performed during the placement and follow-up of the device, respectively. In 5 patients, the device was not deployed because of transesophageal echocardiography (TEE) findings (an exceedingly large defect in 3 patients, partial obstruction of the upper right pulmonary vein by the device in 1, and complex atrial septal anatomy in 1). In the remaining 30 patients, after deployment but before release, the device distorted the atrial septum from the normal vertical orientation to an oblique transverse orientation. Excessive septal distortion (i.e., > or =90 degrees in 1 patient) was associated with device embolization upon release. In other patients, TEE also identified mild splaying of the device on the aortic wall, mild abutment of the device upon the mitral valve, and temporary partial obstruction of pulmonary vein flow. Color Doppler revealed residual shunts in 21 of 29 patients immediately after release, but in none of 15 patients at 1-year follow-up. Transesophageal echocardiography is essential to ensure proper Amplatzer device placement. Distortion of the atrial septum and Amplatzer device orientation occur before release but resolve on release from the delivery cable. Small residual shunts are common early, but they resolve in 6 to 12 months.

Age- and sex-based nomograms from coronary artery calcium scores as determined by electron beam computed tomography.

We present data for 18,785 patients undergoing electron beam computed tomography, dividing them by sex and age (using 5-year age increments) to determine coronary artery calcium scores representing the 50th and 75th percentiles for each group. Because risk stratification is an integral part of determining therapies for coronary artery disease, age- and sex-based scores may be more clinically useful than total coronary artery calcium scores alone.