Childhood leukemia: a genetic disease!

Cancer affects 1 in every 500 children before the age of 14. Little is known about the etiology of this heterogeneous group of diseases despite the fact that they constitute the major cause of death by disease among this population. Because of its relatively higher prevalence, most of the work done in pediatric oncogenetics has been focused on leukemias, particularly acute lymphoblastic leukemia (ALL). Although it is now well accepted that genetic variations play a significant role in determining individual's cancer susceptibility, few studies have explored genetic susceptibility to childhood leukemia with respect to polymorphisms. The main biological mechanisms contributing to cancer susceptibility can be grouped into broad categories : (1) cellular growth and differentiation, (2) DNA replication and repair, (3) xenobiotic metabolism, (4) apoptosis, (5) oxidative stress response and (6) cell cycle. To evaluate whether candidate genes in these pathways are involved in childhood leukemogenesis, we conducted association studies. We showed that leukemogenesis in children may be associated with genetic variants and that the combination of genotypes seems to be more predictive of risk than either of them independently. These results indicate that the genetic investigation of several enzymes (or metabolic pathways) is needed to explain the physiopathology of childhood leukemia because of the complexity of the environment and that of the inter-individual variability in cancer susceptibility.     

Obesity in Children: Recent Advances in Energy Metabolism and Body Composition

In this paper we review recent advances in energy metabolism and body composition studies in pre-pubescent children and the relationship to childhood obesity. Our review on energy expenditure focusses on studies of total energy expenditure using doubly labeled water, the role of energy expenditure in the development of obesity, and the determinants of resting energy expenditure in children. The relatively few studies that have examined the regulation of energy and macronutrient intake in children are also reviewed. In terms of body composition, we focus on recent methodological studies that have developed existing techniques for application to the pediatric population, including dual energy X-ray absorptiometry and bioelectrical resistance. Lastly, we review existing information relating to measurement and alteration of body fat distribution in children.     

Childhood Adversities and Adult Headache in Poland and Germany

Objective

Various childhood adversities have been found to be associated with chronic pain in adulthood. However, associations were moderate in most studies, i.e. odds ratios (OR) were between one and two.

Method

An internet survey was performed in 508 Polish and 500 German subjects. A total of 19 childhood adversities were selected and their associations with headaches explored. Age, gender and country were included as potential confounders, as well as their two-way interaction with the risk factors.

Results

Two strong risk factors were identified. (1) A combined score for physical and emotional neglect showed an odds ratio (OR) of 2.78 (p < .002) to the frequency of headache in adulthood as a main effect. (2) Father having had chronic pain showed an OR of 4.36 (p < .001) with headache in adulthood for women, but not for men (OR = 0.86, p < .556). The majority of the examined childhood adversities were not associated with adult headache, neither when tested individually nor as a sum score.

Conclusion

This study confirms results from previous ones that childhood adversities may play a role in the development of adult headache, but it is a rather minor one. Contrary to other studies, neglect turned out to be one of the strongest predictors.     

小儿慢性胃炎的消化道外表现(附864 例报道)

目的:分析和总结小儿慢性胃炎的消化道外表现。方法:选择2008年1月~2008年10月哈尔滨医科大学附属第二医院儿科门诊诊治的经腹部胃区叩诊法确诊为慢性胃炎的患儿864例,建立随访卡片,分析和总结其消化道内及消化道外的临床表现。结果:864例患儿常见的消化道症状依次为腹痛、恶心呕吐、便秘、上腹压痛。消化道外表现依次为头痛、刀枪刺、鼻出血、胸痛、多动抽动、手足搐搦。消化道外表现的发病率并不低于消化道表现,特别是头痛的发病率高达58.54%。腹痛、恶心呕吐症状缓解得最快,其次是头痛、头晕、胸闷、胸痛,多动症状较晚缓解,腹部叩痛的消失时间最晚。结论:小儿慢性胃炎的胃肠道外表现广泛存在,且极易与脑炎、心肌炎误诊,值得关注。头痛、胸痛的产生原因可能与内脏-内脏之间的牵涉痛有关。     

Arsenic trioxide and neuroblastoma cytotoxicity

The majority of aggressive forms of the childhood tumor neuroblastoma can with current treatment protocols not be cured and possess a major challenge in pediatric oncology. After initial rounds of chemotherapy, surgery and irradiation, which in most cases result in tumor regression, these aggressive neuroblastomas relapse and frequently develop drug resistance. As approximately 50% of the children with neuroblastoma have an aggressive form, there is a compelling demand for new treatment strategies. Arsenic trioxide has the capacity to kill multidrug-resistant neuro-blastoma cells in vitro and in vivo and the drug is currently being evaluated in clinical trials. In this report we discuss the background to the use of arsenic trioxide in cancer therapy and the currently known mechanisms by which arsenic trioxide kills human neuroblastoma cells.     

Recurrent Abdominal Pain, Medical Intervention, and Biofeedback: What Happened to the Biopsychosocial Model?

Recurrent abdominal pain (RAP) is a significant and common problem among pediatric populations. Based on results from randomized controlled trials there are no established efficacious treatments for this disorder. Biofeedback (BFB) and other psychological treatments offer logically appealing alternatives or adjuncts to medical interventions and there is some evidence to support their use. This paper presents a typical case of RAP that exemplifies how the lack of integration of the biopsychosocial model may result in less than optimal treatment. Specifically, it demonstrates that the patient was exposed to potentially risky treatments that lack evidence to support their use and were not beneficial. Although there was evidence of psychological involvement early in the treatment, this was only attended to following numerous medical trials and exploratory surgery over three years. The patient was finally referred for BFB and during a course of seven sessions over five months that variously included heart rate variability and skin temperature feedback along with extensive home practice of paced breathing and hand warming the patient achieved significant symptom reduction and improved coping abilities. This case vividly illustrates the need for multidisciplinary collaboration and full implementation and integration of the biopsychosocial model of health and illness.     

Biofeedback training and human functional state control

Biofeedback (BFB) training paradigm has outstanding place among various approaches to non-phrarmacological human functional state correction. Being an universal way for voluntary self-regulation of physiological functions, it is characterized by efficacy, accessibility and absence of side effects. However, the lack of fundamental knowledge about the BFB mechanisms leads to existence of numerous difficulties and problems that seriously limit the BFB possibilities. Most difficulties seem to concern the problem of adequate choice of BFB type or parameter being voluntary controlled via feedback signals. Some ways to solve this problem are drown on the base of general systems theory. It is shown that BFB procedures could be especially effective in conditions of close interaction between the BFB mechanisms and the central regulatory mechanisms. Such interaction could be reacheb by utilization of certain characteristics of brain electrical activity reflected in the electroencephalogram (EEG). The most perspective seems to be the utilization of discrete narrow band EEG spectral components, individual resonance EEG oscillators or some correlates of human EEG amplitude modulation processes.     

Clinical studies of lactoferrin in children

Much has been learned in recent years about the mechanisms by which breastfeeding improves child health and survival. However, there has been little progress in using these insights to improve pediatric care. The aim of this study was to review all clinical studies of lactoferrin (LF) in children in an effort to determine which interventions may improve pediatric care or require further research. We conducted a systematic and critical review of published literature and found 19 clinical studies that have used human or bovine LF for different outcomes: iron metabolisms and anemia (6 studies), fecal flora (5 studies), enteric infections (3 studies), common pediatric illnesses (1 study), immunomodulation (3 studies), and neonatal sepsis (1 study). Although the efficacies have varied in each trial, the main finding of all published studies is the safety of the intervention. Protection against enteric infections and neonatal sepsis are the most likely biologically relevant activities of LF in children. Future studies on neonatal sepsis should answer critically important questions. If the data from these sepsis studies are proven to be correct, it will profoundly affect the treatment of low birth weight neonates and will aid in the reduction of child mortality worldwide.     

Scavenger receptor class B type 1 regulates neuroblastoma cell proliferation,migration and invasion

Neuroblastoma (NB) is an extra cranial pediatric embryonal tumor most prevalent in children less than 1 year of age. NB accounts for 7% of all pediatric cancers but accounts for 15% of all childhood cancer deaths. Scavenger receptor class B type 1 (SR-B1), a mediator of cellular cholesterol uptake, is overexpressed in and have been linked to the aggressiveness of many cancers. Nevertheless, no studies have so far investigated the relationship between SR-B1 and NB. Elucidation of receptors that promote NB may pave the way for discovery of new therapeutic targets. Here we show that inhibition of SR-B1 reduced cell survival, migration and invasion, and cholesterol content in NB cell lines. Additionally analysis of SR-B1 levels in NB patient biopsies using the R2: Genomics Analysis and Visualization Platform showed that high SR-B1 expression correlated with decreased overall and event-free survival.     

Helicobacter pylori infection and childhood

Pediatric-based Helicobacter?pylori research continues to contribute significantly to our understanding of both clinical and pathophysiological aspects of this infection. Here, we review the published pediatric H.?pylori literature from April 2009-March 2010. Analysis of pediatric H.?pylori strains continues to suggest that cagA(+) and cagPAI competent strains are less prevalent than in adult isolates. Studies from the Middle East report a high H.?pylori prevalence and intrafamilial transmission. Data continue to show a lack of association between H.?pylori and recurrent abdominal pain of childhood, gastroesophageal reflux disease, and growth retardation. Recent probiotic trials have not shown a benefit on H.?pylori eradication in children, while sequential therapy remains an attractive therapeutic eradication strategy in children, which requires validation in different geographic regions.     

The role of genetic risk factors in arterial ischemic stroke in pediatric and adult patients: a critical review

The incidence of arterial ischemic stroke (AIS) in childhood (about 2–13 per 100,000 children a year) is much lower than the incidence in the adult population. Still, adverse outcomes of acute brain ischemia in childhood include death (10 % of AIS children), neurological sequel, epileptic seizures (over 50 %) and recurrence (over 20 %). The knowledge of childhood stroke etiopathogenesis is still insufficient and the diagnostic and therapeutic procedures—controversial. Risk factors for childhood stroke differ from those observed in adults due to differing exposure to external risk factors. The most frequently reported risk factors for pediatric ischemic stroke are cerebral arteriopathies and vascular malformations, cardiac diseases, infections, traumas and metabolic diseases. Because of its multifactorial etiology pediatric AIS probably has a multigenic inheritance pattern. The genetic susceptibility to AIS may be determined by specific polymorphic variants encoding markers of hemostasis regulation and they are some of the most important targets in searching for genetic determinants in pediatric AIS. The authors have reviewed the recent literature on risk factors of childhood ischemic stroke with the focus on genetic factors like polymorphisms of genes encoding coagulation factors II, V, VII and XIII, MTHFR, fibrinogen beta, and compared them with the results performed in adult patients.     

Consensus and Controversy Regarding Osteoporosis in the Pediatric Population

ObjectiveTo review current consensus and controversy surrounding the diagnosis and treatment of osteoporosis in childhood and adolescence.MethodsThe medical literature was reviewed with emphasis on the importance of early skeletal health, risk factors for bone fragility, and the diagnosis and management of children at risk for osteoporosis.ResultsChildhood and adolescence are critical periods for optimizing bone growth and mineral accrual. Bone strength is determined by bone size, geometry, quality, and mass—variables that are influenced by genetic factors, activity, nutrition, and hormones. For children with genetic skeletal disorders or chronic disease, bone growth and mineral accrual may be compromised, increasing the lifetime risk of osteoporosis. The goal for the clinician is to identify children at greatest risk for future fragility fracture. Bone densitometry and turnover markers are challenging to interpret in children. Prevention and treatment of bone fragility in children are less well established than in adults. Optimizing nutrition and activity may not restore bone health, but the drug armamentarium is limited. Sex steroid replacement has not proven effective in restoring bone mass in patients with anorexia nervosa or exercise-associated amenorrhea. Bisphosphonates can increase bone mass and may reduce bone pain and fractures, most convincingly in patients with osteogenesis imperfecta. Further studies are needed to establish the safety, efficacy, and optimal drug, duration, and dosage in pediatric patients.ConclusionBone health during the first 2 decades contributes to the lifetime risk of osteoporosis. Further research is needed to develop evidence-based recommendations for the diagnosis and treatment of osteoporosis in childhood. (Endocr Pract. 2007;13:513-520)     

Prognosis of children with malignant pheochromocytoma. Report of 2 cases and review of the literature

Malignant pheochromocytomas are rare in childhood and the prognosis of children with this tumor is not well known. We present 2 pediatric observations of malignant pelvic pheochromocytoma. Symptoms in both cases were headache and hypertension. The tumor invaded the sacral bone. Angiogram helped to localize the tumor and metastases, and allowed preoperative embolization of the tumor in 1 case. The first child underwent incomplete surgical resection, (131)I-MIBG therapy and radiotherapy, and is still alive 2 years after diagnosis. The second child died from metastatic invasion a few weeks after discovery of the tumor. We reviewed previous reports of children with malignant pheochromocytomas (30 cases). Primary tumor was extraadrenal in 50% of cases. The 3-year survival rate was 73 +/- 9% (mean +/- SD). Apart from surgical resection, no particular treatment appeared to be more effective than others in reducing mortality.     

Combinatorics of the breakage-fusion-bridge mechanism

The breakage-fusion-bridge (BFB) mechanism was proposed over seven decades ago and is a source of genomic variability and gene amplification in cancer. Here we formally model and analyze the BFB mechanism, to our knowledge the first time this has been undertaken. We show that BFB can be modeled as successive inverted prefix duplications of a string. Using this model, we show that BFB can achieve a surprisingly broad range of amplification patterns. We find that a sequence of BFB operations can be found that nearly fits most patterns of copy number increases along a chromosome. We conclude that this limits the usefulness of methods like array CGH for detecting BFB.     

Post-traumatic Stress Disorder in children and adolescents: from Sigmund Freud's "trauma" to psychopathology and the (Dys)metabolic syndrome.

Post-traumatic Stress Disorder (PTSD) is an anxiety syndrome that develops after exposure to traumatic life events. Symptoms include re-experience of the initial trauma, avoidance of stimuli associated with the trauma and symptoms of excessive arousal. Neuroendocrine studies in adults with PTSD have demonstrated that basal cerebrospinal fluid (CSF) CRH levels are elevated and urinary cortisol levels are variable--low in the majority of cases--whereas other studies demonstrate no differences in urinary and plasma cortisol concentrations. Urinary catecholamine excretion is higher in PTSD patients than those of control subjects and other psychiatric disorders. Children may differ from adults in their psychologic and physiologic responses to severe stressors. Also, exposure to stress during critical periods of development may have irreversible effects on behavioral maturation and may affect specific vulnerable brain areas, altering CNS development. Similar to findings in adult studies, PTSD in children is characterized by increased sympathetic nervous system (SNS) activity, as indicated by elevated norepinephrine levels in the periphery. High cortisol levels in urine or saliva have been reported in most studies of childhood PTSD, while prospective longitudinal studies concerning the natural history of neuroendocrine changes in pediatric PTSD after an acute stressor are limited. The identification of neurobiologic changes in response to early adverse experiences is of major importance for the prognosis, prevention, management, and treatment of children and adolescents at risk for or suffering from PTSD.     

Behavioral disorders as unusual presentation of pediatric extraventricular neurocytoma: report on two cases and review of the literature

Background

Extraventricular neurocytomas (EVNs) are rare parenchymal brain tumors, distinct from central neurocytomas that are typically located within the supratentorial ventricular system. Seizures and headache represent the most common symptoms of extraventricular neurocytomas in the cerebral hemisphere both in adult and pediatric population.

Case presentation

We describe two cases of pediatric EVN with clinical onset characterized by behavioral and attention deficit/ hyperactivity disorders. The association between behavioral/attention disorders in childhood and the presence of a frontal neurocytoma has never been described before. Furthermore, inappropriate levels of inattention, hyperactivity and impulsivity are common among the neurobehavioral and developmental disorders in childhood. We reviewed 43 pediatric cases of extraventricular neurocytoma included in the PubMed database and their clinical presentation, and we never found this unusual relationship.

Conclusion

In childhood, the attention/hyperactivity disorders seem to be often over-diagnosed. When these deficits are more subtle and do not well-fit in a specific neurocognitive disorder, the clinicians should have a suspicion that they might mask the clinical features of a frontal lesion. This paper is focused on the clinical presentation of the extraventricular neurocytoma and the possible organic etiology of an attention and hyperactivity deficit.

     

Aurora Kinases as Druggable Targets in Pediatric Leukemia: Heterogeneity in Target Modulation Activities and Cytotoxicity by Diverse Novel Therapeutic Agents

Leukemia is the most common pediatric malignancy, constituting more than 30% of all childhood cancers. Although cure rates have improved greatly, approximately one in five children relapse and poor survival rates post relapse remain a challenge. Given this, more effective and innovative therapeutic strategies are needed in order to improve prognosis. Aurora kinases, a family of serine/threonine kinases essential for the regulation of several mitotic processes, have been identified as potential targets for cancer therapeutics. Elevated expression of Aurora kinases has been demonstrated in several malignancies and is associated with aberrant mitotic activity, aneuploidy and alterations in chromosomal structure and genome instability. Based on this rationale, a number of small molecule inhibitors have been formulated and advanced to human studies in the recent past. A comparative analysis of these agents in cytotoxicity and target modulation analyses against a panel of leukemia cells provides novel insights into the unique mechanisms and codependent activity pathways involved in targeting Aurora kinases, constituting a distinctive preclinical experimental framework to identify appropriate agents and combinations in future clinical studies.     

Socioeconomic status and adiposity in childhood: a systematic review of cross-sectional studies 1990-2005

Background: Sobal and Stunkard's review (1989) of 34 studies from developed countries published after 1941, found inconsistent relationships between socioeconomic status (SES) and childhood adiposity. Inverse associations (36%), no associations (38%), and positive associations (26%) were found in similar proportions. In view of the trends in pediatric obesity, the relationship between SES and adiposity may have changed. Objective: To describe the cross‐sectional association between SES and adiposity in school‐age children from western developed countries in epidemiological studies since 1989. Methods and Procedures: PubMed database was searched to identify potentially relevant publications. Epidemiological studies from western developed countries presenting cross‐sectional data on the bivariate association between an SES indicator and objectively measured adiposity in childhood (5–18 years), carried out after 1989 were included. SES indicators included parental education, parental occupation, family income, composite SES, and neighborhood SES. Results: Forty‐five studies satisfied the review criteria. SES was inversely associated with adiposity in 19 studies (42%), there was no association in 12 studies (27%), and in 14 studies (31%) there was a mixture of no associations and inverse associations across subgroups. No positive SES‐adiposity associations were seen in unadjusted analyses. With parental education as the SES indicator, inverse associations with adiposity were found in 15 of 20 studies (75%). Discussion: Research carried out within the past 15 years finds that associations between SES and adiposity in children are predominately inverse, and positive associations have all but disappeared. Research is needed to understand the mechanisms through which parental social class influences childhood adiposity.     

Role of BMI-associated loci identified in GWAS meta-analyses in the context of common childhood obesity in European Americans

Obesity is a serious health concern for children and adolescents, particularly in Western societies, where its incidence is now considered to have reached epidemic proportions. A number of genetic determinants of adult BMI have already been established through genome wide association studies (GWAS), most recently from the GIANT meta-analysis of such datasets combined. In this current study of European Americans, we examined the 32 loci detected in that GIANT study in the context of common childhood obesity within a cohort of 1,097 cases (defined as BMI ≥95th percentile), together with 2,760 lean controls (defined as BMI <50th percentile), aged between 2 and 18 years old. Nine of these single-nucleotide polymorphims (SNPs) yielded at least nominal evidence for association with common childhood obesity, namely at the FTO, TMEM18, NRXN3, MC4R, SEC16B, GNPDA2, TNNI3K, QPCTL, and BDNF loci. However, overall 28 of the 32 loci showed directionally consistent effects to that of the adult BMI meta-analysis. We conclude that among the 32 loci that have been reported to associate with adult BMI in the largest meta-analysis of BMI to date, at least nine also contribute to the determination of common obesity in childhood in European Americans, as demonstrated by their associations in our pediatric cohort.     

Neuropsychology, plasticity and childhood epilepsy

Epilepsy is one of the most frequent childhood disorders. While most cases are well controlled, approximately 30-50% are resistant to medical treatment. In these cases, neurosurgery may be an option. Since 1979, our team at the Sainte-Justine Hospital in Montreal has studied the impact of epilepsy on the psycho-motor and cognitive development of the affected children. The aim of a first series of studies was to explore the extent and limits of cerebral plasticity by investigating the neuropsychological sequelae of early versus late callosotomy and hemispherectomy. In keeping with the plasticity hypothesis, the results revealed that the children who were operated before puberty showed fewer deficits than those operated during adolescence or adulthood. However, the compensatory mechanisms available to them appeared to be limited with respect to the nature and complexity of the information they can process. For instance, young children having undergone section of the corpus callosum resembled individuals born without a corpus callosum (callosal agenesis) in that there did not show the typical disconnection deficits seen in adult 'split-brain' patients. However, they exhibited deficits on tasks requiring interhemispheric integration of motor and visuo-motor information. By the same token, hemispherectomy patients were still able to make visual judgements in their 'blind' visual field but they were found to be impaired on a variety of visual and auditory tasks (localization of a sound sources in space) requiring the participation of both hemispheres. In a second series of studies, carried out in collaboration with a Parisian team, we intended to describe the neuropsychological profile of focal epilepsies, specifically frontal and temporal epilepsy. Contrary to the common belief that childhood epilepsy would result in diffuse impairments, we were able to demonstrate that children manifest the same localized deficits as adult patients. In studies presently underway in our laboratories, we make use of functional neuroimaging techniques such as high density electrophysiology, optical imaging and magnetoencephalography to investigate pre-and postoperative language and memory functions and to study the impact of epilepsy on brain maturation.