Epigenetic deregulation in pediatric acute lymphoblastic leukemia

Similar to most cancers, genome-wide DNA methylation profiles are commonly altered in pediatric acute lymphoblastic leukemia (ALL); however, recent observations highlight that a large portion of malignancy-associated DNA methylation alterations are not accompanied by related gene expression changes. By analyzing and integrating the methylome and transcriptome profiles of pediatric B-cell ALL cases and primary tissue controls, we report 325 genes hypermethylated and downregulated and 45 genes hypomethylated and upregulated in pediatric B-cell ALL, irrespective of subtype. Repressed cation channel subunits and cAMP signaling activators and transducers are overrepresented, potentially indicating a reduced cellular potential to receive and propagate apoptotic signals. Furthermore, we report specific DNA methylation alterations with concurrent gene expression changes within individual ALL subtypes. The ETV6-RUNX1 translocation was associated with downregulation of ASNS and upregulation of the EPO-receptor, while Hyperdiploid patients (> 50 chr) displayed upregulation of B-cell lymphoma (BCL) members and repression of PTPRG and FHIT. In combination, these data indicate genetically distinct B-cell ALL subtypes contain cooperative epimutations and genome-wide epigenetic deregulation is common across all B-cell ALL subtypes.

Balloon cell melanoma: a case report with polarized and non-polarized dermatoscopy and dermatopathology

Balloon cell melanoma is a rare melanoma subtype, with only one previous case with dermatoscopy published. It is often non-pigmented, leading to diagnostic difficulty, and there is a tendency for lesions to be thick at diagnosis. We report a case of balloon cell melanoma on the forearm of a 61-year-old man with both polarized and non-polarized dermatoscopy and dermatopathology. It presented as a firm pale nodule with focal eccentric pigmentation. The clinical images evoke a differential diagnosis of dermatofibroma, dermal nevus, Spitz nevus and basal cell carcinoma as well as melanoma. This melanoma was partially pigmented due to a small, pigmented superficial spreading component on the edge of the non-pigmented balloon cell nodule, prompting further evaluation. In retrospect there was the clue to malignancy of polarizing-specific white lines (chrysalis structures) and polymorphous vessels, including a pattern of dot vessels. The reticular lines exclude basal cell carcinoma, polarizing-specific white lines are inconsistent with the diagnosis of dermal nevus and their eccentric location is inconsistent with both Spitz nevus and dermatofibroma. Excision biopsy was performed, revealing a superficial spreading melanoma with two distinct invasive components, one of atypical non-mature epithelioid cells and the other an amelanotic nodular component, comprising more than 50% of the lesion, characterized by markedly distended epithelioid melanocytes showing pseudo-xanthomatous cytoplasmic balloon cell morphology. A diagnosis of balloon cell melanoma, Breslow thickness 1.9 mm, mitotic rate 3 per square millimeter was rendered. Wide local excision was performed, as was sentinel lymph node biopsy, which was negative.

Transfer of maternal antibodies against avian influenza virus in mallards (Anas platyrhynchos)

Maternal antibodies protect chicks from infection with pathogens early in life and may impact pathogen dynamics due to the alteration of the proportion of susceptible individuals in a population. We investigated the transfer of maternal antibodies against avian influenza virus (AIV) in a key AIV host species, the mallard (Anas platyrhynchos). Combining observations in both the field and in mallards kept in captivity, we connected maternal AIV antibody concentrations in eggs to (i) female body condition, (ii) female AIV antibody concentration, (iii) egg laying order, (iv) egg size and (v) embryo sex. We applied maternity analysis to the eggs collected in the field to account for intraspecific nest parasitism, which is reportedly high in Anseriformes, detecting parasitic eggs in one out of eight clutches. AIV antibody prevalence in free-living and captive females was respectively 48% and 56%, with 43% and 24% of the eggs receiving these antibodies maternally. In both field and captive study, maternal AIV antibody concentrations in egg yolk correlated positively with circulating AIV antibody concentrations in females. In the captive study, yolk AIV antibody concentrations correlated positively with egg laying order. Female body mass and egg size from the field and captive study, and embryos sex from the field study were not associated with maternal AIV antibody concentrations in eggs. Our study indicates that maternal AIV antibody transfer may potentially play an important role in shaping AIV infection dynamics in mallards.

Accepting risk in the acceleration of drug development for rare cancers.

Rare cancers collectively contribute a disproportionate fraction of the total burden of cancer. The oncology community is increasingly facing small numbers of patients with each cancer subtype, requiring cooperation and collaboration to complete multicentre trials that advance knowledge and patient care. At the same time, new insights into the biology of rare cancers have led to an explosion in knowledge and development of targeted agents. These insights and techniques are set to revolutionise the care of patients with cancer. However, drug development strategies and the availability of new agents for rare cancers are at risk of stalling owing to the ever-increasing complexity and costs of clinical trials. Finding solutions to these problems is imperative to the future of cancer care. We propose that a greater degree of risk sharing is needed than is currently accepted to enable the use of new methods with confidence, and to keep pace with scientific advancement.

Autism spectrum disorder symptoms in children with ADHD: a community-based study

This study examined the prevalence of autism spectrum disorder (ASD) symptoms in a community-based sample of children with attention-deficit/hyperactivity disorder (ADHD) and non-ADHD controls. We also examined the relationship between ASD symptoms and ADHD subtype, ADHD symptom severity and child gender. Participants were 6-10-year-old children (164 ADHD; 198 non-ADHD control) attending 43 schools in Melbourne, Australia, who were participating in the Children's Attention Project. ADHD was assessed in two stages using the parent and teacher Conners' 3 ADHD index and the Diagnostic Interview Schedule for Children IV (DISC-IV). ASD symptoms were identified using the Social Communication Questionnaire (SCQ). Unadjusted and adjusted linear and logistic regression examined continuous and categorical outcomes, respectively. Children with ADHD had more ASD symptoms than non-ADHD controls (adjusted mean difference=4.0, 95% confidence interval (CI) 2.8; 5.3, p<0.001, effect size=0.7). Boys with ADHD had greater ASD symptom severity than girls with ADHD (adjusted mean difference=2.9, 95% CI 0.8; 5.2, p=0.01, effect size=0.4). Greater ADHD symptom severity was associated with greater ASD symptom severity (regression co-efficient=1.6, 95% CI 1.2; 2.0, p<0.001). No differences were observed by ADHD subtype. Greater hyperactive/impulsive symptoms were associated with greater ASD symptoms (regression coefficient=1.0; 95% CI 0.0; 2.0, p=0.04) however, this finding attenuated in adjusted analyses (p=0.45). ASD symptoms are common in children with ADHD. It is important for clinicians to assess for ASD symptoms to ensure appropriate intervention.

Subtyping based on readiness and confidence: the identification of help-seeking profiles for gamblers accessing web-based counselling

BACKGROUND AND AIMS: Problem gamblers are not a homogeneous group and recent data suggest that subtyping can improve treatment outcomes. This study administered three readiness rulers and aimed to identify subtypes of gamblers accessing a national web-based counselling service based on these rulers. METHODS: Participants were 1204 gamblers (99.4% problem gamblers) who accessed a single session of web-based counselling in Australia. Measures included three readiness rulers (importance, readiness and confidence to resist an urge to gamble), demographics and the Problem Gambling Severity Index (PGSI). RESULTS: Gamblers reported high importance of change [mean = 9.2, standard deviation (SD) = 1.51] and readiness to change (mean = 8.86, SD = 1.84), but lower confidence to resist an urge to gamble (mean = 3.93, SD = 2.44) compared with importance and readiness. The statistical fit indices of a latent class analysis identified a four-class model. Subtype 1 was characterized by a very high readiness to change and very low confidence to resist an urge to gamble (n = 662, 55.0%) and subtype 2 reported high readiness and low confidence (n = 358, 29.7%). Subtype 3 reported moderate ratings on all three rulers (n = 139, 11.6%) and subtype 4 reported high importance of change but low readiness and confidence (n = 45, 3.7%). A multinomial logistic regression indicated that subtypes differed by gender (P < 0.001), age (P = 0.01), gambling activity (P < 0.05), preferred mode of gambling (P < 0.001) and PGSI score (P < 0.001). CONCLUSIONS: Problem gamblers in Australia who seek web-based counselling comprise four distinct subgroups based on self-reported levels of readiness to change, confidence to resist the urge to gamble and importance of change.

Anxiety in children with attention-deficit/hyperactivity disorder

OBJECTIVES: Although anxiety is common in children with attention-deficit/hyperactivity disorder (ADHD), it is unclear how anxiety influences the lives of these children. This study examined the association between anxiety comorbidities and functioning by comparing children with ADHD and no, 1, or ≥2 anxiety comorbidities. Differential associations were examined by current ADHD presentation (subtype). METHODS: Children with diagnostically confirmed ADHD (N = 392; 5-13 years) were recruited via 21 pediatrician practices across Victoria, Australia. Anxiety was assessed by using the Anxiety Disorders Interview Schedule for Children-IV. Functional measures included parent-reported: quality of life (QoL; Pediatric Quality of Life Inventory 4.0), behavior and peer problems (Strengths and Difficulties Questionnaire), daily functioning (Daily Parent Rating of Evening and Morning Behavior), and school attendance. Teacher-reported behavior and peer problems (Strengths and Difficulties Questionnaire) were also examined. Linear and logistic regression controlled for ADHD severity, medication use, comorbidities, and demographic factors. RESULTS: Children with ≥2 anxiety comorbidities (n = 143; 39%) had poorer QoL (effect size: -0.8) and more difficulties with behavior (effect size: 0.4) and daily functioning (effect size: 0.3) than children without anxiety (n = 132; 36%). Poorer functioning was not observed for children with 1 anxiety comorbidity (n = 95; 26%). Two or more anxiety comorbidities were associated with poorer functioning for children with both ADHD-Inattentive and ADHD-Combined presentation. CONCLUSIONS: Children with ADHD demonstrate poorer QoL, daily functioning and behavior when ≥2 anxiety comorbidities are present. Future research should examine whether treating anxiety in children with ADHD improves functional outcomes.

Swine influenza virus PA and neuraminidase gene reassortment into human H1N1iInfluenza Virus is associated with an altered pathogenic phenotype linked to increased MIP-2 expression

Swine are susceptible to infection by both avian and human influenza viruses, and this feature is thought to contribute to novel reassortant influenza viruses. In this study, the influenza virus reassortment rate in swine and human cells was determined. Coinfection of swine cells with 2009 pandemic H1N1 virus (huH1N1) and an endemic swine H1N2 (A/swine/Illinois/02860/09) virus (swH1N2) resulted in a 23% reassortment rate that was independent of α2,3- or α2,6-sialic acid distribution on the cells. The reassortants had altered pathogenic phenotypes linked to introduction of the swine virus PA and neuraminidase (NA) into huH1N1. In mice, the huH1N1 PA and NA mediated increased MIP-2 expression early postinfection, resulting in substantial pulmonary neutrophilia with enhanced lung pathology and disease. The findings support the notion that swine are a mixing vessel for influenza virus reassortants independent of sialic acid distribution. These results show the potential for continued reassortment of the 2009 pandemic H1N1 virus with endemic swine viruses and for reassortants to have increased pathogenicity linked to the swine virus NA and PA genes which are associated with increased pulmonary neutrophil trafficking that is related to MIP-2 expression. IMPORTANCE: Influenza A viruses can change rapidly via reassortment to create a novel virus, and reassortment can result in possible pandemics. Reassortments among subtypes from avian and human viruses led to the 1957 (H2N2 subtype) and 1968 (H3N2 subtype) human influenza pandemics. Recent analyses of circulating isolates have shown that multiple genes can be recombined from human, avian, and swine influenza viruses, leading to triple reassortants. Understanding the factors that can affect influenza A virus reassortment is needed for the establishment of disease intervention strategies that may reduce or preclude pandemics. The findings from this study show that swine cells provide a mixing vessel for influenza virus reassortment independent of differential sialic acid distribution. The findings also establish that circulating neuraminidase (NA) and PA genes could alter the pathogenic phenotype of the pandemic H1N1 virus, resulting in enhanced disease. The identification of such factors provides a framework for pandemic modeling and surveillance.

Service use in children aged 6-8 years with attention deficit hyperactivity disorder

OBJECTIVE: This study investigated prevalence, types and predictors of professional service use in families of children identified with attention deficit hyperactivity disorder (ADHD) in the community.

DESIGN: SETTING: children with ADHD were identified through 43 schools using parent and teacher screening questionnaires (Conners 3 ADHD Index) followed by case confirmation using the Diagnostic Interview Schedule for Children Version IV. Parents completed a survey about professional service use in the last 12 months.

MAIN OUTCOME MEASURES: data on variables potentially associated with service use were collected from parents (interview and questionnaires), teachers (questionnaires) and children (direct assessment). Logistic regression was used to examine predictors of service use in univariate and multivariable analyses.

RESULTS: The sample comprised 179 children aged 6-8 years with ADHD. Over one-third (37%) had not received professional services in the last 12 months. The strongest predictors of service use were older child age (adjusted OR=3.0, 95% CI 1.0 to 8.9, p=0.05), and the degree to which the child's behaviour impacted on the family (adjusted OR=2.0, 95% CI 1.3 to 3.3, p=0.007), after controlling for ADHD subtype and severity, externalising comorbidities, academic achievement and parent-reported impairment.

CONCLUSIONS: A substantial proportion of children with ADHD are not accessing professional services. Our findings suggest that the child's age and the impact of the child's behaviour on the family are the strongest predictors of service use. Given the demonstrated benefits from various interventions in ADHD, there is a need to improve case identification and referral for services.

The relationship between divorce and children with AD/HD of different subtypes and comorbidity: results from a clinically referred sample

This study investigated the relationship between divorce and thesymptom profile of children with attention deficit/hyperactivity disorder(AD/HD). The files of 1,201 children from a pediatric practicein Sydney, Australia were used in this study. Children wereaged 6 to 18 years, and were diagnosed with either the inattentiveor combined type of AD/HD. Results show that 213 children hadparents who were divorced. Children with the combined type, andespecially boys with comorbid conduct disorder/oppositional defiantdisorder (CD/ODD) were more common in the divorced group,and children of the inattentive type with comorbid learning disabilitieswere overrepresented in nondivorced families. Results suggestthat divorce is associated with disruptive behavior patterns inchildren with AD/HD. The importance of including marital status asan important correlate in AD/HD treatment outcomes is discussed.

Child AD/HD severity and psychological functioning in relation to divorce, remarriage, multiple transitions and the quality of family relationships

Both Attention-Deficit/Hyperactivity Disorder (AD/HD) and divorce are very prevalent in western societies, and they may occur together. AD/HD is generally viewed as a neurobiological disorder, which has led to a commonly held belief that social-environmental factors play little role in the symptom profile of children diagnosed with the disorder. This study investigated the association between parental divorce, remarriage, multiple transitions, the quality of relationships with family members and the psychological well-being of children and adolescents with AD/HD. First, differences in children’s AD/HD symptom profiles in relation to parents’ divorce status (single/multiple divorce) and family composition (single parent/stepfamily) were examined. Second, the association between the quality of children’s relationships with each family member and parents’ marital status (divorced/non-divorced) and family composition was investigated. In addition, age, gender and AD/HD subtype differences were assessed. Third, the association between the quality of children’s interactions with family members and children’s AD/HD symptom profile was explored. No significant differences in children’s behavioural profiles were found in terms of parents’ divorce status. Living in stepfamilies was associated with greater AD/HD severity and social malfunctioning. Disruptive parent–child and sibling relationships were found to be related to children’s age, gender, AD/HD subtype and parents’ marital status. Further, poor interactions with family members correlated with children’s AD/HD severity and psychological well-being. In summary, divorce, remarriage and the quality of relationships with family members are important correlates of the symptom profile of children with AD/HD, and this emphasises the need for special treatment modules for these families.