Balancing the benefits and harms of thyroid cancer surveillance in survivors of Childhood, adolescent and young adult cancer: Recommendations from the international Late Effects of Childhood Cancer Guideline Harmonization Group in collaboration with the PanCareSurFup Consortium.

Radiation exposure to the thyroid gland during treatment of childhood, adolescent and young adult cancer (CAYAC) may cause differentiated thyroid cancer (DTC). Surveillance recommendations for DTC vary considerably, causing uncertainty about optimum screening practices. The International Late Effects of Childhood Cancer Guideline Harmonization Group, in collaboration with the PanCareSurFup Consortium, developed consensus recommendations for thyroid cancer surveillance in CAYAC survivors. These recommendations were developed by an international multidisciplinary panel that included 33 experts in relevant medical specialties who used a consistent and transparent process. Recommendations were graded according to the strength of underlying evidence and potential benefit gained by early detection and appropriate management. Of the two available surveillance strategies, thyroid ultrasound and neck palpation, neither was shown to be superior. Consequently, a decision aid was formulated to guide the health care provider in counseling the survivor. The recommendations highlight the need for shared decision making regarding whether to undergo surveillance for DTC and in the choice of surveillance modality.

Controversies in the management of Graves' disease in children.

Graves' disease (GD) is the most prevalent cause of thyrotoxicosis in children. Because spontaneous and lasting resolution of this condition occurs in only a minority of patients, most pediatric patients with GD will need radioactive iodine treatment (131I) or thyroidectomy. Whereas the medication propylthiouracil (PTU) had been used in the past, only methimazole (MMI) should be now used in children, as PTU is associated with an unacceptable risk of liver failure. However, MMI may be associated minor and major side effects, which may be minimized using lower doses. An area of controversy involves the optimal duration of antithyroid drug (ATD) therapy. For some children, the prolonged use of antithyroid drugs is a valid approach, but for most, this will not increase the chance of remission. When 131I is administered, dosages should be greater than 150 uCi/gm of thyroid tissue, with higher dosages needed for larger glands. Considering that there will be low-level whole body radiation exposure associated with 131I, this treatment is viewed as controversial by some and should be avoided in young children. When surgery is performed, near-total or total thyroidectomy is the recommended procedure. Complications for thyroidectomy in children are considerably higher than in adults. Thus, an experienced thyroid surgeon is needed when children have surgery. Overall, when different treatment options for GD are considered, the benefits, risks and viewpoints of the family need to be considered and discussed in full.

Prevalence and risk factors for disrupted circadian rhythmicity in children with optic nerve hypoplasia.

BACKGROUND/AIMS: Children with optic nerve hypoplasia (ONH) have visual impairment and may have hypopituitarism and developmental delay. Children with ONH have also been reported to have abnormal sleep-wake cycles. We assessed the incidence and nature of sleep-wake abnormalities in children with ONH. METHODS: Rest-activity patterns were assessed in 23 children with ONH using actigraphy, which is a non-invasive method for continuously monitoring activity. The children also had formal assessment of pituitary function, visual acuity measurements, assessment of papillary responsiveness, MRI scans of the head and assessment of neurocognitive function. RESULTS: Sufficient actigraphy data were obtained on 19 of the children. Analysis of expressed rhythmicity revealed normal rest-activity patterns in 13 children (68%). Of the six children (32%) with abnormal rhythmicity, three had fragmented sleep, one had free-running rest-activity cycles and two were arrhythmic. Of the children with normal rhythmicity, the following were found: hypoplastic corpus callosum in 30%, growth hormone deficiency in 53%, hypothyroidism in 23%, adrenal insufficiency in 30%, diabetes insipidus in 0% and developmental delay in 15%. Of the children with abnormal rhythmicity, the following were found: hypoplastic corpus callosum in 66% (p>0.05), severe visual impairment in 100% (p=0.006), abnormal pupillary responsiveness in 85% (p=0.0084), cognitive impairment in 100% (p=0.04) and multiple hormonal deficiencies in 66% (p=0.03). CONCLUSIONS: Abnormal rest-activity rhythmicity patterns are present in 30% of children with ONH. The best predictors of abnormal rhythmicity are severe vision impairment, abnormal pupillary responsiveness, developmental delay and multiple hormonal deficiencies.

A1 adenosine receptors mediate hypoglycemia-induced neuronal injury.

The cellular mechanisms that lead to neuronal death following glucose deprivation are not known, although it is recognized that hypoglycemia can lead to perturbations in intracellular calcium ([Ca2+]i) levels. Recently, activation of A1 adenosine receptors (A1AR) has been shown to alter [Ca2+]i and promote neuronal death. Thus, we examined if A1AR activation contributes to hypoglycemia-induced neuronal injury using rat cortical neurons. First, we observed that hypoglycemia was associated with large increases in neuronal adenosine release. Next, decreased neuronal viability was seen with progressive reduction in glucose concentration (25, 6, 3, 0.75 and 0 mM). Using the calcium-sensitive dye, Fluo-3, we observed both acute and long-term changes in relative [Ca2+]i during hypoglycemic conditions. Demonstrating a role for adenosine in this process, both the loss in neuronal viability and the early changes in [Ca2+]i were reversed by treatment with A1AR antagonists (8-cyclopentyl, 1,3-dipropylxanthine; 9-chloro-2-(2-furyl)(1,2,4)-triazolo(1,5-c)quinazolin-5-amine; and N-cyclopentyl-9-methyladenine). We also found that hypoglycemia induced the expression of the pro-apoptotic enzyme, caspase-3, and that A1AR antagonism reversed hypoglycemia-induced caspase-3 activity. Collectively, these data show that hypoglycemia induces A1ARs activation leading to alterations in [Ca2+]i, which plays a prominent role in leading to hypoglycemia-induced neuronal death.

Mechanisms and clinical significance of circadian rhythms in children.

Circadian rhythms are endogenously generated rhythms with a period length of about 24 hours. A biologic clock in the hypothalamic suprachiasmatic nuclei is responsible for the generation of circadian rhythms. Notable examples of the circadian rhythms include the sleep-wake cycle and rhythms in hormone production. Abnormalities of the circadian system include biologic clock lesions that result in arrhythmic behavior and irregular sleep patterns. Abnormalities of the circadian system also occur when there is desynchronization of clock phase with that of the outside world, resulting in conditions such as "jet-lag." Numerous aspects of human physiology are greatly influenced by the time of day, as is the pathogenesis of illness. During development, the circadian system becomes functional at early stages and is regulated by photic information. With the continued elucidation of circadian system influences on human physiology and illness, it is anticipated that circadian biology will have an increasingly important impact on the clinical care of children.

Influences of adenosine on the fetus and newborn.

Few signaling molecules have the potential to influence the developing mammal as the nucleoside adenosine. In contrast to most neurotransmitters, adenosine is released by all cells and is present in all tissues. The adenosinergic system is therefore not dependent on the presence of mature synaptic structures or an intact autonomic nervous system for its release. However, similar to other signaling molecules, adenosine levels are dynamically regulated and increase with increased tissue activity, hypoxia, or stress. Local adenosine concentrations thus provide a "humoral barometer" of acute changes in cellular physiology. The receptors that transduce adenosine action include A1, A2a, A2b, and A3 adenosine receptors. These receptors differ in their affinities for adenosine and in patterns of tissues expression. During development A1 adenosine receptors (A1ARs) are especially important, and A1ARs are among the earliest receptors expressed in the embryonic brain and heart. In the developing heart, the adenosinergic system is the dominant regulator of fetal cardiac function and A1AR activation inhibits cardiac cell division leading to cardiac hypoplasia. In the forming central nervous system, A1AR activation potently inhibits the development of axons and can lead to leukomalacia. These recent data suggest that adenosine is an important modulator of mammalian development.

A1 adenosine receptor activation inhibits neurite process formation by Rho kinase-mediated pathways.

A1 adenosine receptors (A1ARs) are expressed in the brain during critical periods of neurogenesis and neuronal differentiation. To examine influences of A1AR activation on neuronal development we studied the effects of A1AR activation on process growth in PC12 cells expressing A1ARs and in primary cultures of cortical and hippocampal neurons. In PC12 cells, we found that A1AR activation potently inhibited nerve growth factor (NGF)-induced neurite growth and induced stress fiber formation. A1ARs action was not mediated by inhibition of p44/42 MAP kinase activity, as inhibition of MEK/MAP kinase had no effects on A1AR action. When Rho kinase activity was blocked, A1AR agonists no longer inhibited neurite growth and stress fiber formation was blocked. In neurons, A1AR activation also inhibited process growth, and A1AR action was also mediated by Rho kinase. These data show that A1AR activation inhibits neurite growth and that the inhibitory effects of A1AR are dependent on Rho kinase.

Rho kinases play an obligatory role in vertebrate embryonic organogenesis.

Rho-associated kinases (Rho kinases), which are downstream effectors of RhoA GTPase, regulate diverse cellular functions including actin cytoskeletal organization. We have demonstrated that Rho kinases also direct the early stages of chick and mouse embryonic morphogenesis. We observed that Rho kinase transcripts were enriched in cardiac mesoderm, lateral plate mesoderm and the neural plate. Treatment of neurulating embryos with Y27632, a specific inhibitor of Rho kinases, blocked migration and fusion of the bilateral heart primordia, formation of the brain and neural tube, caudalward movement of Hensen's node, and establishment of normal left-right asymmetry. Moreover, Y27632 induced precocious expression of cardiac alpha-actin, an early marker of cardiomyocyte differentiation, coincident with the upregulated expression of serum response factor and GATA4. In addition, specific antisense oligonucleotides significantly diminished Rho kinase mRNA levels and replicated many of the teratologies induced by Y27632. Thus, our study reveals new biological functions for Rho kinases in regulating major morphogenetic events during early chick and mouse development.

Arrhythmicity in a child with septo-optic dysplasia and establishment of sleep-wake cyclicity with melatonin.

We identified a 3-year-old child with septo-optic dysplasia with arrhythmic activity patterns. To assess whether melatonin could improve rest-activity patterns, 0.1 mg was administered orally at 19:00 hours. After therapy onset, normal rest-activity patterns appeared. These observations show that melatonin can restore normal rhythmicity in the absence of a normally functioning circadian clock.

Ontogeny of humoral heart rate regulation in the embryonic mouse.

Catecholamines, acetylcholine, and adenosine are known to influence cardiac function, yet the effects of these agents on mammalian embryonic myocardium are largely unknown. To address this issue, we compared the chronotrophic effects of adenosinergic, adrenergic, and muscarinic agents on cultured murine embryos from postcoital day (PC) 8.0, when the fusing heart tubes first begin to beat, to PC 14, when cardiogenesis is essentially complete. At PC 8.0 and older, A(1)-adenosine receptor (A(1)AR) activation significantly decreased heart rates. Adrenergic stimulation caused modest increases in heart rates (145-155% of baseline) beginning at PC 9.0. Muscarinic activation decreased heart rates only after PC 13. When receptor gene expression was examined, A(1)ARs and beta(1)ARs were expressed in isolated hearts as early as PC 9.0, and beta(2)ARs and m(2)-muscarinic receptor genes were expressed at PC 11.0. These results identify the adenosinergic system as the earliest and most potent regulator of embryonic cardiac function and show that prenatal responsiveness to catecholamines and acetylcholine develops at later embryonic stages.

Inhibition of cell proliferation in the embryonic myocardium by A1 adenosine receptor activation.

A1 adenosine receptors (A1ARs) are expressed in the embryonic heart and influence cardiac function at early developmental stages. To test if A1ARs also affect cardiac structural development, we examined the effects of A1AR activation on heart formation. When pregnant mice were treated with the A1AR agonist, N(6)-cyclopentyladenosine (CPA), fetuses showed marked reduction of ventricular size and manifested features of heart failure. Suggesting that these findings represent direct effects on embryos, CPA treatment of cultured whole murine embryos resulted in cardiac hypoplasia. When rates of cell division and cell death in the heart were examined, we found decreases in cardiac cell proliferation following A1AR activation. In contrast, no changes in numbers or distribution of apoptotic cells were seen. Collectively, these data show that A1AR activation inhibits cardiac cell proliferation and can lead to cardiac hypoplasia. These data identify adenosine as a potential regulator of cardiac cell division during early development.

The use of radioactive iodine in the management of hyperthyroidism in children.

Graves' disease is the most common form of hyperthyroidism in childhood. Current treatment options include antithyroid medications, surgery, and radioactive iodine. Medical therapy is generally associated with long term remission rates of less than 25% and a small risk of serious adverse reactions that include hepatic failure and bone marrow suppression. Total thyroidectomy is associated with very high cure rates and a small risk of hypoparathyroidism and recurrent laryngeal nerve damage. When radioactive iodine is used at appropriate doses, there is a very high cure rate without increased risks of thyroid cancer or genetic damage. Because of the theoretical risk of thyroid cancer after thyroid irradiation in individuals less than 20 years of age, relatively high doses of radioactive iodine should be administered to minimize the persistence of residual thyroid tissue.

Regulation of leptin release and lipolysis by PGE2 in rat adipose tissue.

The role of eicosanoids formed by adipose tissue from rats was examined in the presence of the specific cyclooxygenase-2 inhibitor NS-398. This agent totally blocked the release of prostaglandin E2 (PGE2) by rat adipose tissue over a 24-h incubation in primary culture. The final concentration of PGE2 after 24 h was 12 nM, and half-maximal inhibition of PGE2 formation required 35 nM NS-398. While inhibition of PGE2 formation by NS-398 had no effect on basal leptin release or lipolysis, it enhanced the lipolytic action of 10 nM isoproterenol by 36%. The in vivo administration of PGE2 doubled serum leptin. PGE2 also directly stimulated leptin release by rat adipose tissue incubated in the presence of 25 nM dexamethasone, which inhibited endogenous PGE2 formation by 94%. The inhibition of lipolysis as well as the stimulation of leptin release by PGE2 were mimicked by N6-cyclopentyladenosine (CPA). These data indicate that exogenous PGE2 can stimulate leptin release by adipose tissue when the basal formation of PGE2 is blocked by dexamethasone. However, while the endogenous formation of PGE2 does not appear to regulate basal lipolysis or leptin release, it may play a role in the activation of lipolysis by catecholamines.

Tissue-specific expression of GTPas RalA and RalB during embryogenesis and regulation by epithelial-mesenchymal interaction.

RalA and RalB are members of the Ras-like GTP-binding protein family. To investigate if Ral GTPases play a role in development, temporal and spatial patterns of RalA and RalB gene expression were examined during embryogenesis. RalA and RalB had tissue-specific pattern of expression in developing organs. Both GTPases were expressed in endodermal derivatives in the digestive tract, kidney, mesonephros, gonad, adrenal gland, trachea, and blood vessels. RalA and RalB were also expressed in the ectodermal derivatives in the brain, spinal cord, ganglia, eye, skin, hair, whiskers, and teeth. RalA and RalB were also expressed in some mesodermal tissues including the lung mesenchyme and myocardium. Tissue recombination experiments showed that of Ral expression was increased by epithelial-mesenchymal interaction in the lung, indicating that Ral expression is functionally regulated. These data identify that RalA and RalB as inducible GTPases in the developing embryo.

Dexamethasone treatment of virilizing congenital adrenal hyperplasia: the ability to achieve normal growth.

OBJECTIVE: To assess whether treatment of virilizing congenital adrenal hyperplasia (CAH) with long-acting glucocorticoids is associated with favorable growth outcomes. METHOD: We examined the long-term growth of 17 boys and 9 girls with CAH treated with dexamethasone (.27 +/-.01 mg/m(2)/day). RESULTS: For individuals with comparable bone age (BA) and chronological age (CA) at the onset of dexamethasone therapy, males were 2.8 +/-.8 years (mean +/- standard error of the mean; n = 13) and females were 2.4 +/- 1.0 years (n = 6). Males were treated for 7.3 +/- 1.1 years (DeltaCA) over which time the change in BA (DeltaBA) was 7.0 +/- 1.3 years, and the change in height age (DeltaHA) was 6.9 +/- 1.1 years. Females were treated for 6.8 +/- 1.3 years, over which time the DeltaBA was 6.5 +/- 1.0 years, and the DeltaHA was 6.3 +/-.8 years. During treatment 17 ketosteroid excretion rates were normal for age and 17-hydroxyprogesterone values were 69.6 +/- 18 ng/dL. Testicular enlargement was first detected at 10.7 +/-.8 years and breast tissue at 9.9 +/- 1.2 years. Three boys and 1 girl had final heights of 171. 8 +/- 6 cm and 161 cm, respectively, compared with midparental heights of 176.1 +/- 4.1 cm and 160 cm. Predicted adult heights for 6 other boys and 5 girls were 176.8 +/- 2.0 cm and 161.4 +/- 2.8 cm, respectively, compared with midparental heights of 174.6 +/- 1.4 cm and 158.2 +/- 2.0 cm. Statural outcomes were less favorable for 7 children started on dexamethasone when BAs were considerably advanced, although height predictions increased during therapy. CONCLUSIONS: These observations show that children treated with dexamethasone for CAH can achieve normal growth with the convenience of once-a-day dosing in most cases.congenital adrenal hyperplasia, dexamethasone, growth.

Developing circadian rhythmicity.

Circadian rhythms are endogenously generated rhythms with a period length of about 24-hours. Evidence gathered over the past decade indicates that the circadian timing system develops prenatally, and the suprachiasmatic nuclei, the site of a circadian clock, is present by midgestation in human and nonhuman primates. Recent evidence also shows that the circadian system of primate infants is responsive to light at very premature stages and that low intensity lighting can regulate the developing clock. After birth, there is progressive maturation of the circadian system outputs, with pronounced rhythms in sleep-wake and hormone secretion generally developing after 2 months of age. With the continued elucidation of circadian system development and influences on human physiology and illness, it is anticipated that consideration of circadian biology will become an increasingly important component of neonatal care.

Are A3 adenosine receptors expressed in the brain?

An increasing number of reports suggest a role for A3 adenosine receptors (A3ARs) in mediating adenosine action in the central nervous system. However, studies of A3AR localization in the brain have yet to be performed. To provide insights into the central sites of A3AR action, we compared patterns of A1 and A3AR mRNA and binding site expression in the brains of rats, mice and humans. We also assessed whether A3 agonists are selective for A3ARs. Whereas it was possible to detect high-level A1AR expression in many brain regions, it was not possible to detect either A3AR gene or binding site expression in the central nervous system. When we examined the affinities of the A3AR agonists CI-IAB-MECA and IAB-MECA for A1ARs, we found that these compounds bound to A1ARs with high affinity. These observations suggest that studies using A3-agonists need to consider potential effects of A1ARs activation, as A1ARs are abundantly expressed in the nervous system whereas A3AR expression in the brain cannot be directly demonstrated.

Programmed cell death in the developing heart: regulation by BMP4 and FGF2.

Programmed cell death, or apoptosis, plays an important role in embryonic development. To provide new insights into the role of programmed cell death in cardiac development, we examined the hearts of the murine embryos from E9.5 to postnatal day 3. Using terminal transferase-mediated dUTP nick end-labeling assays, apoptosis was detected in the endocardial cushions and myocardium from E11.5 to postnatal day 3 (P3). In the ventricular myocardium, more apoptotic cells were observed in the left than right ventricles throughout embryonic and early postnatal development. Apoptosis was also present in the trabeculae and papillary muscles of the ventricles. In the outflow tract, cell death was present in the endocardial cushions before they fuse to form the conotruncal septum (E11.5-E12. 5) and reached a peak intensity when the conotruncal septum formed (E13.5). In the atrioventricular (AV) endocardial cushions, cell death was detected in the fusion seam of the cushion tissues at E12. 5 and E13.5 during AV septation. When the patterns of apoptosis were compared with patterns of cell division, we found that programmed cell death occurred in the areas in the endocardial cushions and trabeculae where rates of cell proliferation were low. We also found that programmed cell death was regulated by the growth factors, BMP4 and FGF2, in vitro. BMP4 induced, whereas FGF2 inhibited, apoptosis in both endocardial cushions and ventricular myocardium. Overall, our observations show that there is apoptosis in the regions where fusion or remodeling of tissues occurs. We also show that cardiac programmed cell death can be influenced by growth factors.