Sensitivity and Specificity of Whole-body MRI for the Detection of Pediatric Malignancy.

Children with cancer often present with general and nonspecific symptoms leading to initial diagnostic workup inclusive of clinical imaging. Various sequences of magnetic resonance imaging (MRI) are becoming more available for diagnostic imaging. However, there is currently a dearth of literature quantifying the sensitivity and specificity of whole-body MRI in identifying pediatric malignancy. In this study, a retrospective analysis was performed of pediatric whole-body MRI inclusive of short tau inversion recovery sequence conducted at an academic pediatric medical center from 2013 to 2018. Kappa statistics were used to evaluate the diagnostic agreement between MRI results and the gold standard diagnostic study of the respective final diagnosis. Sensitivity, specificity, false-positive, and false-negative estimates were provided with joint 90% confidence regions. One hundred forty-two patients received a whole-body MRI during the study period. The sensitivity of whole-body MRI in detecting malignancy was found to be 93.8% with a specificity of 93.4%. The positive and negative predictive values were determined to be 65.2% and 99.1%, respectively. Our findings suggest that whole-body MRI may be of value as an initial diagnostic tool for pediatric malignancy. Larger multicenter collaboration will be needed to further support these data.

Co-morbid conditions in use of recombinant tissue plasminogen activator (rt-PA) for the treatment of acute ischaemic stroke.

BACKGROUND: The objective of this study was to characterize the comorbidities in a population of patients with an acute ischaemic stroke, comparing patients that received recombinant tissue plasminogen activator (rt-PA) to those that did not receive rt-PA. METHOD: In a retrospective sample of 663 patients admitted for acute ischaemic stroke, this study analysed the effects of co-morbid conditions in the use of rt-PA. It determined non-cerebrovascular risk factors (comorbidities) that differentiate patients who received rt-PA from those who did not receive rt-PA. RESULT: Patients with a history of carotid stenosis, CHF and previous strokes are significantly (p < 0.05) associated with high risk of not receiving rt-PA. A significant number of patients with a history of hypertension and smoking received rt-PA (p < 0.05). CONCLUSION: The findings indicate that certain risk factors including carotid stenosis, CHF and previous stroke history impact the treatment of patients with acute ischaemic stroke, specifically the decision to administer rt-PA. Treatment with rt-PA is dependent on stroke severity and onset to treatment time, but the findings suggest that rt-PA use may also depend on patient comorbidities.

Sex-related differences in mast cell activity and doxorubicin toxicity: a study in spontaneously hypertensive rats.

Clinically, girls appear to be more sensitive than boys to the cardiotoxic effects of doxorubicin, whereas the opposite may be true for adults. To identify and characterize potential sex-related differences, adult male and female spontaneously hypertensive rats (SHR; some ovariectomized [OVX]) received 1 mg/kg of doxorubicin or saline iv weekly for 9, 10, or 12 weeks. Weight gain was slower in treated males. Serum concentrations of cholesterol and triglycerides increased and those of albumin decreased in both sexes, but changes were more pronounced in treated males. Treated males had significantly more severe cardiomyopathy scores and higher serum levels of cTnT than females. The increased cardiotoxicity was accompanied by higher numbers of cardiac mast cells (MCs) and percentage of cardiac MCs undergoing degranulation. Doxorubicin-treated OVX animals had significantly increased numbers of cardiac MCs, more severe myocardial lesions, and elevated serum concentrations of cTnT compared to doxorubicin-treated normal female SHR. The severity of cardiac lesions in the OVX female was similar to that observed in doxorubicin-treated males. This study demonstrated the presence of sex-related differences in the cardiotoxic effects elicited by doxorubicin and identified variations in the level of cardiac MC activity as a factor which could possibly contribute to the male-female dissimilarity.

The influence of age on serum concentrations of cardiac troponin I: results in rats, monkeys, and commercial sera.

Cardiac troponins serve as serum biomarkers of myocardial injury. The current study examined the influence of age on serum concentrations of cardiac troponin I (cTnI). An ultrasensitive immunoassay was used to monitor cTnI concentrations in Sprague-Dawley (SD) rats and Erythrocebus patas monkeys of different ages. The mean cTnI concentrations were highest in 10-day-old rats compared to 25-, 40-, and 80-day-old SD rats. Cardiomyocyte remodeling was apparent in hearts from 10-day-old SD rats as evident by hypercellularity, irregularly shaped nuclei, and moderate numbers of myocytes undergoing mitosis and apoptosis. The mean concentration of cTnI in 5 newborn monkeys was considerably higher than that of three 1-year-old monkeys. Evidence of cardiomyocyte remodeling was also observed in these newborn hearts (loss of myofibrils and cytoplasmic vacuolation). Commercial animal serum samples were also analyzed. The concentrations of cTnI detected in fetal equine and porcine serum were considerably higher than that found in adult equine and porcine serum samples Likewise, fetal bovine serum had higher cTnI concentrations (>2,400 pg/ml) than did adult caprine and laprine samples (2.5-2.7 pg/ml). The present study found age-related differences in cTnI concentrations, with higher levels occurring at younger ages. This effect was consistent across several animal species.

Methamphetamine Activates Toll-Like Receptor 4 to Induce Central Immune Signaling within the Ventral Tegmental Area and Contributes to Extracellular Dopamine Increase in the Nucleus Accumbens Shell.

Methamphetamine (METH) is a globally abused, highly addictive stimulant. While investigations of the rewarding and motivational effects of METH have focused on neuronal actions, increasing evidence suggests that METH can also target microglia, the innate immune cells of the central nervous system, causing release of proinflammatory mediators and therefore amplifying the reward changes in the neuronal activity induced by METH. However, how METH induces neuroinflammatory responses within the central nervous system (CNS) is unknown. Herein, we provide direct evidence that METH creates neuroinflammation, at least in part, via the activation of the innate immune Toll-like receptor 4 (TLR4). Biophysical studies revealed that METH bound to MD-2, the key coreceptor of TLR4. Molecular dynamics simulations showed METH binding stabilized the active heterotetramer (TLR4/MD-2)2 conformation. Classic TLR4 antagonists LPS-RS and TAK-242 attenuated METH induced NF-κB activation of microglia, whereas added MD-2 protein boosted METH-induced NF-κB activation. Systemically administered METH (1 mg/kg) was found to specifically up-regulate expression of both CD11b (microglial activation marker) and the proinflammatory cytokine interleukin 6 (IL-6) mRNAs in the ventral tegmental area (VTA), but not in either the nucleus accumbens shell (NAc) or prefrontal cortex (PFC). Systemic administration of a nonopioid, blood-brain barrier permeable TLR4 antagonist (+)-naloxone inhibited METH-induced activation of microglia and IL-6 mRNA overexpression in VTA. METH was found to increase conditioned place preference (CPP) as well as extracellular dopamine concentrations in the NAc, with both effects suppressed by the nonopioid TLR4 antagonist (+)-naloxone. Furthermore, intra-VTA injection of LPS-RS or IL-6 neutralizing antibody suppressed METH-induced elevation of extracellular NAc dopamine. Taken together, this series of studies demonstrate that METH-induced neuroinflammation is, at least in part, mediated by TLR4-IL6 signaling within the VTA, which has the downstream effect of elevating dopamine in the NAc shell. These results provide a novel understanding of the neurobiological mechanisms underlying acute METH reward that includes a critical role for central immune signaling and offers a new target for medication development for treating drug abuse.

Costal and Auricular Cartilage Grafts for Nasal Reconstruction: An Anatomic Analysis.

OBJECTIVES: The aim of this study was to measure the length, width, and surface area of costal and auricular cartilage harvested for grafting in rhinoplasty and nasal reconstruction. We also compared the sizes of ear cartilage grafts harvested from the anterior and posterior approaches. METHODS: Fifty-eight nasal reconstructive surgeries requiring rib or ear cartilage were performed by 2 facial plastic surgeons from February 2015 through January 2016. Among the 57 cases that met inclusion criteria, they comprised of 33 costal cartilage grafts and 24 auricular cartilage grafts (17 via anterior approach and 7 via posterior approach). RESULTS: The mean length, width, and surface area for the auricular cartilage grafts were 3.39 cm, 1.22 cm, and 4.38 cm2, respectively. The mean length, width, and surface area of the costal cartilage grafts were 4.21 cm, 1.46 cm, and 17.87 cm2, respectively. The differences in length, width, and surface area between the anterior versus posterior approach groups were all statistically significant. CONCLUSIONS: In our study, ear cartilage grafts harvested from the posterior approach had significantly greater length, width, and surface area. While this analysis has several limitations, it sets quantitative norms for costal and auricular cartilage harvest that can aid in surgical planning.

Electromagnetic Navigational Bronchoscopy Reduces the Time Required for Localization and Resection of Lung Nodules.

OBJECTIVE: The aims of the study were to evaluate electromagnetic navigational bronchoscopy (ENB) and computed tomography-guided placement as localization techniques for minimally invasive resection of small pulmonary nodules and determine whether electromagnetic navigational bronchoscopy is a safer and more effective method than computed tomography-guided localization. METHODS: We performed a retrospective review of our thoracic surgery database to identify patients who underwent minimally invasive resection for a pulmonary mass and used either electromagnetic navigational bronchoscopy or computed tomography-guided localization techniques between July 2011 and May 2015. RESULTS: Three hundred eighty-three patients had a minimally invasive resection during our study period, 117 of whom underwent electromagnetic navigational bronchoscopy or computed tomography localization (electromagnetic navigational bronchoscopy = 81; computed tomography = 36). There was no significant difference between computed tomography and electromagnetic navigational bronchoscopy patient groups with regard to age, sex, race, pathology, nodule size, or location. Both computed tomography and electromagnetic navigational bronchoscopy were 100% successful at localizing the mass, and there was no difference in the type of definitive surgical resection (wedge, segmentectomy, or lobectomy) (P = 0.320). Postoperative complications occurred in 36% of all patients, but there were no complications related to the localization procedures. In terms of localization time and surgical time, there was no difference between groups. However, the down/wait time between localization and resection was significant (computed tomography = 189 minutes; electromagnetic navigational bronchoscopy = 27 minutes); this explains why the difference in total time (sum of localization, down, and surgery) was significant (P < 0.001). CONCLUSIONS: We found electromagnetic navigational bronchoscopy to be as safe and effective as computed tomography-guided wire placement and to provide a significantly decreased down time between localization and surgical resection.

Spontaneous peripartum coronary artery dissection presentation and outcome.

OBJECTIVE: The objective of this study was to determine whether spontaneous peripartum coronary artery dissection (SPCAD) is a cause of acute myocardial infarction in women. METHODS: Patients with SPCAD reported in the recent literature were analyzed to elucidate the clinically relevant characteristics of this condition. RESULTS: Forty-seven cases of SPCAD are described. Patient characteristics include the following: mean age, 33.5 ± 5.2 years; gravity, 2.7 (95% confidence interval, 1.8-3.5); mean gestational age if prepartum, 32.5 ± 4.2 weeks (range, 23-36 weeks); and mean onset if postpartum, 22.9 ± 26.1 days (range, 3-90 days). Only 17 patients (36%) reported a cardiac risk factor, with the most frequent being smoking. All presented with characteristic ischemic pain; 25% of patients were hemodynamically unstable; and 81% of initial electrocardiograms demonstrated ST-elevation myocardial infarctions. The left coronary artery system was involved 81% of the time. Thirty percent of patients were managed conservatively or with thrombolytic therapy, whereas 34% received emergent percutaneous cardiac intervention and 36% required bypass surgery. There were no maternal deaths. Long-term follow-up revealed good cardiac function in the majority of patients, although 3 women required heart transplantation. CONCLUSIONS: SPCAD can occur weeks before or after delivery and should be considered in women presenting during the peripartum period with acute chest pain.

An expert opinion on pharmacologic approaches to reducing the cardiotoxicity of childhood acute lymphoblastic leukemia therapies.

INTRODUCTION: Acute lymphoblastic leukemia (ALL) is the most common hematologic malignancy in children. Treatment-related cardiac damage is progressive and often difficult to reverse. Strategies to minimize cardiotoxicity during treatment are crucial to prevent severe lasting effects on health and quality of life. AREAS COVERED: This comprehensive review covers the pathophysiology and various presentations, both clinical and subclinical, of treatment-induced cardiotoxicity and characteristics associated with increased risk of cardiac dysfunction in childhood ALL survivors. Additionally, contemporary prevention strategies such as limiting cumulative anthracycline dose, altering drug administration schedule, the use of anthracycline structural analogs, liposomal encapsulated anthracyclines, cardioprotective agents and nutritional supplements are critically analyzed. Finally, this review covers the management options of chemotherapy-induced damage and other treatment-related cardiotoxicity. EXPERT OPINION: Higher lifetime cumulative doses of anthracyclines, younger age at diagnosis, longer follow-up, female sex, higher dose rates and cranial irradiation are associated with more severe cardiotoxic effects. Long-term adverse effects of both anthracycline and non-anthracycline chemotherapeutic agents are becoming an increasing focus during treatment of childhood malignancies. There must be a careful balance between achieving remission of childhood ALL while avoiding the development of another often-fatal illness, heart failure.

Metabolic regulatory clues from the naked mole rat: toward brain regulatory functions during stroke.

Resistance to tissue hypoxia is a robust fundamental adaptation to low oxygen supply, and represents a novel neuroscience problem with significance to mammalian physiology as well as human health. With the underlying mechanisms strongly conserved in evolution, the ability to resist tissue hypoxia in natural systems has recently emerged as an interesting model in mammalian physiology research to understand mechanisms that can be manipulated for the clinical management of stroke. The extraordinary ability to resist tissue hypoxia by the naked mole rat (NMR) indicates the presence of a unique mechanism that underlies the remarkable healthy life span and exceptional hypoxia resistance. This opens an interesting line of research into understanding the mechanisms employed by the naked mole rat (Heterocephalus glaber) to protect the brain during hypoxia. In a series of studies, we first examined the presence of neuroprotection in the brain cells of naked mole rats (NMRs) subjected to hypoxic insults, and then characterized the expression of such neuroprotection in a wide range of time intervals. We used oxygen nutrient deprivation (OND), an in vitro model of resistance to tissue hypoxia to determine whether there is evidence of neuronal survival in the hippocampal (CA1) slices of NMRs that are subjected to chronic hypoxia. Hippocampus neurons of NMRs that were kept in hypoxic condition consistently tolerated OND right from the onset time of 5h. This tolerance was maintained for 24h. This finding indicates that there is evidence of resistance to tissue hypoxia by CA1 neurons of NMRs. We further examined the effect of hypoxia on metabolic rate in the NMR. Repeated measurement of metabolic rates during exposure of naked mole rats to hypoxia over a constant ambient temperature indicates that hypoxia significantly decreased metabolic rates in the NMR, suggesting that the observed decline in metabolic rate during hypoxia may contribute to the adaptive mechanism used by the NMR to resist tissue hypoxia. This work is aimed to contribute to the understanding of mechanisms of resistance to tissue hypoxia in the NMR as an important life-sustaining process, which can be translated into therapeutic interventions during stroke.

Treatment-related cardiotoxicity in survivors of childhood cancer.

Treatment advances and higher participation rates in clinical trials have rapidly increased the number of survivors of childhood cancer. However, chemotherapy and radiation treatments are cardiotoxic and can cause cardiomyopathy, conduction defects, myocardial infarction, hypertension, stroke, pulmonary oedema, dyspnoea and exercise intolerance later in life. These cardiotoxic effects are often progressive and irreversible, emphasizing a need for effective prevention and treatment to reduce or avoid cardiotoxicity. Medical interventions, such as angiotensin-converting enzyme inhibitors, ß-blockers, and growth hormone therapy, might be used to treat cardiotoxicity in childhood cancer survivors. Preventative strategies should include the use of dexrazoxane, which provides cardioprotection without reducing the oncological efficacy of doxorubicin chemotherapy; less-toxic anthracycline derivatives and the use of antioxidant nutritional supplements might also be beneficial. Continuous-infusion doxorubicin provides no benefit over bolus infusion in children. Identifying patient-related (for example, obesity and hypertension) and drug-related (for example, cumulative dose) risk factors for cardiotoxicity could help tailor treatments to individual patients. However, all survivors of childhood cancer are at increased risk of cardiotoxicity, suggesting that survivor screening recommendations for assessment of global risk of premature cardiovascular disease should apply to all survivors. Optimal, evidence-based monitoring strategies and multiagent preventative treatments still need to be identified.

Cardiac effects in perinatally HIV-infected and HIV-exposed but uninfected children and adolescents: a view from the United States of America.

INTRODUCTION: Human immunodeficiency virus (HIV) infection is a primary cause of acquired heart disease, particularly of accelerated atherosclerosis, symptomatic heart failure, and pulmonary arterial hypertension. Cardiac complications often occur in late-stage HIV infections as prolonged viral infection is becoming more relevant as longevity improves. Thus, multi-agent HIV therapies that help sustain life may also increase the risk of cardiovascular events and accelerated atherosclerosis. DISCUSSION: Before highly active antiretroviral therapy (HAART), the two-to-five-year incidence of symptomatic heart failure ranged from 4 to 28% in HIV patients. Patients both before and after HAART also frequently have asymptomatic abnormalities in cardiovascular structure. Echocardiographic measurements indicate left ventricular (LV) systolic dysfunction in 18%, LV hypertrophy in 6.5%, and left atrial dilation in 40% of patients followed on HAART therapy. Diastolic dysfunction is also common in long-term survivors of HIV infection. Accelerated atherosclerosis has been found in HIV-infected young adults and children without traditional coronary risk factors. Infective endocarditis, although rare in children, has high mortality in late-stage AIDS patients with poor nutritional status and severely compromised immune systems. Although lymphomas have been found in HIV-infected children, the incidence is low and cardiac malignancy is rare. Rates of congenital cardiovascular malformations range from 5.6 to 8.9% in cohorts of HIV-uninfected and HIV-infected children with HIV-infected mothers. In non-HIV-infected infants born to HIV-infected mothers, foetal exposure to ART is associated with reduced LV dimension, LV mass, and septal wall thickness and with higher LV fractional shortening and contractility during the first two years of life. CONCLUSIONS: Routine, systematic, and comprehensive cardiac evaluation, including a thorough history and directed laboratory assays, is essential for the care of HIV-infected adults and children as cardiovascular illness has become a part of care for long-term survivors of HIV infection. The history should include traditional risk factors for atherosclerosis, prior opportunistic infections, environmental exposures, and therapeutic and illicit drug use. Laboratory tests should include a lipid profile, fasting glucose, and HIV viral load. Asymptomatic cardiac disease related to HIV can be fatal, and secondary effects of HIV infection often disguise cardiac symptoms, so systematic echocardiographic monitoring is warranted.

Pediatric cardiomyopathies: causes, epidemiology, clinical course, preventive strategies and therapies.

Pediatric cardiomyopathies, which are rare but serious disorders of the muscles of the heart, affect at least one in every 100,000 children in the USA. Approximately 40% of children with symptomatic cardiomyopathy undergo heart transplantation or die from cardiac complications within 2 years. However, a significant number of children suffering from cardiomyopathy are surviving into adulthood, making it an important chronic illness for both pediatric and adult clinicians to understand. The natural history, risk factors, prevalence and incidence of this pediatric condition were not fully understood before the 1990s. Questions regarding optimal diagnostic, prognostic and treatment methods remain. Children require long-term follow-up into adulthood in order to identify the factors associated with best clinical practice including diagnostic approaches, as well as optimal treatment approaches. In this article, we comprehensively review current research on various presentations of this disease, along with current knowledge about their causes, treatments and clinical outcomes.