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Clinical scientists are calling for strong partnerships in the provision of evidence-based treatments for child mental health problems in real-world contexts. In the present study, we describe the implementation of a cognitive-behavioral intervention (CBI) to address grade 5 children's anxiety symptoms. The CBI arose from a long-standing partnership between University and Education Department stakeholders. The partnership integrates school-based, evidence-informed treatment delivery with clinical education, and also supports a school-based psychology clinic to provide assessment and treatment services to children attending schools within the catchment area and clinical training for university graduate students. Children in the active condition (N=74) completed the CBI during regular class time, while children in the control condition (N=77) received the standard classroom curriculum. Children's anxiety and depressive symptoms, threat interpretation biases (perceived danger and coping ability), and perceptions of their social skills were assessed before and after condition. Children in the active condition reported significant improvements in self-reported anxiety symptoms, and perceptions of their social skills and coping ability, whereas no significant differences were observed for children in the control condition from pre- to post-assessment. For a subset of children assessed 12 months after the CBI (n=76), symptom improvement remained stable over time and estimates of danger and coping ability showed even greater improvement. Results demonstrate the value of strong stakeholder partnerships in innovative youth mental health services, positive child outcomes, and clinical education., (Copyright © 2015. Published by Elsevier Ltd.)

The present study evaluated the effectiveness of a modified One Session Treatment (OST), which included an e-therapy homework maintenance program over 4 weeks for Blood-Injection-Injury (BII) phobia in children and adolescents. Using a single case, non-concurrent multiple-baseline design, 24 children and adolescents (8-18 years; 7 males, 17 females) with a primary diagnosis of BII phobia were randomly assigned to a one, two or three week baseline prior to receiving OST. Primary outcome measures included diagnostic severity, diagnostic status, and child and parent fear ratings. Secondary outcome measures included avoidance during behavioural avoidance tasks (BAT), global functioning and self and parent reported anxiety, fear and depression. Efficacy was assessed at post-treatment, 1-month, and 3-month follow-up. BII symptoms and diagnostic severity remained relatively stable during the baseline periods and then significantly improved following implementation of the intervention. Treatment response was supported by changes across multiple measures, including child, parent and independent clinician ratings. At post-treatment 8 of the 24 (33.33%) children were BII diagnosis free. Treatment gains improved at follow-ups with 14 (58.33%) children diagnosis free at 1-month follow-up and 15 (62.5%) diagnosis free at 3-month follow-up. Preliminary findings support the effectiveness of a modified OST approach for BII phobic youth with treatment outcomes improving over follow-up intervals., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

Attention bias modification training (ABMT) is a promising treatment for anxiety disorders. Recent evidence suggests that attention training towards positive stimuli, using visual-search based ABMT, has beneficial effects on anxiety and attention biases in children. The present study extends this prior research using distinctive techniques designed to increase participant learning, memory consolidation, and treatment engagement. Fifty-nine clinically anxious children were randomly assigned to the active treatment condition (ATC) (N = 31) or waitlist control condition (WLC) (N = 28). In the ATC, children completed 12 treatment sessions at home on computer in which they searched matrices for a pleasant or calm target amongst unpleasant background pictures, while also engaging in techniques designed to consolidate learning and memory for these search strategies. No contact was made with children in the WLC during the wait period. Diagnostic, parent- and child-reports of anxiety and depressive symptoms, externalising behaviour problems and attention biases were assessed pre- and post-condition and six-months after treatment. Children in the ATC showed greater improvements on multiple clinical measures compared to children in the WLC. Post-treatment gains improved six-months after treatment. Attention biases for angry and happy faces did not change significantly from pre-to post-condition. However, larger pre-treatment attention bias towards threat was associated with greater reduction in anxiety at post-treatment. Also, children who showed greater consolidation of learning and memory strategies during treatment achieved greater improvement in global functioning at post-treatment. Attention training towards positive stimuli using enhanced visual-search procedures appears to be a promising treatment for childhood anxiety disorders., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

In this study of young adolescents' (N = 188, M age  = 11.93, 54.8% females) body dysmorphic disorder (BDD) symptoms, we examined a theoretically-derived model to determine if symptoms could be explained by appearance-related teasing, general peer victimization, and social anxiety. BDD symptoms were assessed as distressing preoccupation with perceived appearance defects, social avoidance, and repeated grooming and appearance checking. Associations were expected to occur via the social-perceptual bias known as appearance-based rejection sensitivity (appearance-RS). The source of appearance teasing was also considered (same-sex vs. cross-sex peers), and age and gender moderation were assessed. As predicted, in a structural equation model, BDD symptoms were higher when adolescents self-reported more appearance teasing and higher social anxiety. Moreover, it was appearance teasing by cross-sex peers, rather than same-sex peers, that was uniquely associated with elevated BDD symptoms. These associations were partially mediated by appearance-RS. Notably, peer-reported general victimization was not associated with BDD symptoms. There was no evidence for gender moderation, but some age moderation was found, with stronger associations usually found among older compared to younger adolescents. The findings suggest that appearance-related social adversity, particularly cross-sex teasing, is linked with greater concerns about rejection due to appearance and, in turn, heightened BDD symptoms. This has important implications for understanding the development and treatment of BDD. Continued research to identify the social experiences and interpretative biases that contribute to BDD symptomology is needed.

Neuroblastoma remains a common cause of pediatric cancer deaths, especially for children who present with advanced stage or recurrent disease. Currently, retinoic acid therapy is used as maintenance treatment to induce differentiation and reduce tumor recurrence following induction therapy for neuroblastoma, but unavoidable side effects are seen. A novel retinoid, UAB30, has been shown to generate negligible toxicities. In the current study, we hypothesized that UAB30 would have a significant impact on multiple neuroblastoma cell lines in vitro and in vivo. Cellular survival, cell-cycle analysis, migration, and invasion were studied using AlamarBlue assays, FACS, and Transwell assays, respectively, in multiple cell lines following treatment with UAB30. In addition, an in vivo murine model of human neuroblastoma was utilized to study the effects of UAB30 upon tumor xenograft growth and animal survival. We successfully demonstrated decreased cellular survival, invasion, and migration, cell-cycle arrest, and increased apoptosis after treatment with UAB30. Furthermore, inhibition of tumor growth and increased survival was observed in a murine neuroblastoma xenograft model. The results of these in vitro and in vivo studies suggest a potential therapeutic role for the low toxicity synthetic retinoid X receptor selective agonist, UAB30, in neuroblastoma treatment., (©2015 American Association for Cancer Research.)

Neuroblastoma is the most common extracranial solid tumor of childhood and is responsible for over 15% of pediatric cancer deaths. Focal adhesion kinase (FAK) is a nonreceptor tyrosine kinase that is important in many facets of neuroblastoma tumor development and progression. The p53 oncogene, although wild type in most neuroblastomas, lacks significant function as a tumor suppressor in these tumors. Recent reports have found that FAK and p53 interact in some tumor types. We have hypothesized FAK and p53 coordinately control each other's expression and also interact in neuroblastoma. In the present study, we showed that not only do FAK and p53 interact but each one controls the expression of the other. In addition, we also examined the effects of FAK inhibition combined with p53 activation in neuroblastoma and showed that these two, in combination, had a synergistic effect on neuroblastoma cell survival. The findings from this present study help to further our understanding of the regulation of neuroblastoma tumorigenesis and may provide novel therapeutic strategies and targets for neuroblastoma and other pediatric solid tumors., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Objective: Although CBT has proven efficacious in the treatment of child social phobia (SP), most children do not present for treatment and child SP may be less responsive to treatment than other anxiety disorders. Intensive, group-based, SP-specific CBT may improve the efficacy of, and access to, treatment for child SP. The aim of this study was to provide a preliminary examination of such a program., Method: Forty Australian children aged 7-12 years (15 male and 25 female) were allocated into treatment and waitlist groups. Clinical interviews to determine diagnostic status were conducted prior to treatment, following treatment and at 6-month follow-up. Parent and child questionnaire measures of child anxiety symptoms, internalizing symptoms, depression, social skills, social competence, and parental social anxiety were administered at the same time points. Treatment was delivered in 4 separate 3-hour sessions conducted over 3 consecutive weekends., Results: At postassessment, 52.4% of children in the treatment group and 15.8% of children in the waitlist group were free of their SP diagnosis. At postassessment, compared to waitlist children, treatment group children demonstrated a greater drop in clinical severity, a greater increase in overall functioning, and held fewer clinical diagnoses. Treatment group children also reported a greater reduction in SP symptoms compared to waitlist children, and treatment group parents reported a greater reduction in child internalizing and anxiety symptoms, a greater increase in child social competence, and a greater decrease in parental SP symptoms, compared to parents of children in the waitlist group. By 6-month follow-up, 76.9% of the treatment group were free of their SP diagnosis and gains on all other measures were maintained., Conclusions: The results of this study are encouraging, and suggest that brief, intensive, group CBT for children with social anxiety is beneficial for many youngsters., (Copyright © 2014. Published by Elsevier Ltd.)

Background: Mutations in microtubule-regulating genes are associated with disorders of neuronal migration and microcephaly. Regulation of centriole length has been shown to underlie the pathogenesis of certain ciliopathy phenotypes. Using a next-generation sequencing approach, we identified mutations in a novel centriolar disease gene in a kindred with an embryonic lethal ciliopathy phenotype and in a patient with primary microcephaly., Methods and Results: Whole exome sequencing data from a non-consanguineous Caucasian kindred exhibiting mid-gestation lethality and ciliopathic malformations revealed two novel non-synonymous variants in CENPF, a microtubule-regulating gene. All four affected fetuses showed segregation for two mutated alleles [IVS5-2A>C, predicted to abolish the consensus splice-acceptor site from exon 6; c.1744G>T, p.E582X]. In a second unrelated patient exhibiting microcephaly, we identified two CENPF mutations [c.1744G>T, p.E582X; c.8692 C>T, p.R2898X] by whole exome sequencing. We found that CENP-F colocalised with Ninein at the subdistal appendages of the mother centriole in mouse inner medullary collecting duct cells. Intraflagellar transport protein-88 (IFT-88) colocalised with CENP-F along the ciliary axonemes of renal epithelial cells in age-matched control human fetuses but did not in truncated cilia of mutant CENPF kidneys. Pairwise co-immunoprecipitation assays of mitotic and serum-starved HEKT293 cells confirmed that IFT88 precipitates with endogenous CENP-F., Conclusions: Our data identify CENPF as a new centriolar disease gene implicated in severe human ciliopathy and microcephaly related phenotypes. CENP-F has a novel putative function in ciliogenesis and cortical neurogenesis., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.)

Background and Objectives: Children of parents with emotional disorders have an increased risk for developing anxiety and depressive disorders. Yet the mechanisms that contribute to this increased risk are poorly understood. The present study aimed to examine attention biases in children as a function of maternal lifetime emotional disorders and maternal attention biases., Methods: There were 134 participants, including 38 high-risk children, and their mothers who had lifetime emotional disorders; and 29 low-risk children, and their mothers without lifetime emotional disorders. Mothers and children completed a visual probe task with emotional face pairs presented for 500 ms., Results: Attention bias in children did not significantly differ solely as a function of whether or not their mothers had lifetime emotional disorders. However, attention bias in high-risk children was significantly related to their mothers' attention bias. Specifically, children of mothers with lifetime emotional disorders showed a greater negative attention bias if their mothers had a greater tendency to direct attention away from positive information., Limitations: This study was cross-sectional in nature, and therefore unable to assess long-term predictive effects. Also, just one exposure duration of 500 ms was utilised., Conclusion: Attention bias for negative information is greater in offspring of mothers who have lifetime emotional disorders and a reduced positive bias, which could be a risk marker for the development of emotional disorders in children.

Background: Delirium is relatively common after lung transplantation, although its prevalence and prognostic significance have not been systematically studied. The purpose of the present study was to examine pretransplant predictors of delirium and the short-term impact of delirium on clinical outcomes among lung transplant recipients., Methods: Participants underwent pretransplant cognitive testing using the Repeatable Battery for the Assessment of Neuropsychological Status and the Trail Making Test. After transplant, delirium was assessed using the Confusion Assessment Method until discharge., Results: Sixty-three patients were transplanted between March and November 2013, of which 23 (37%) developed delirium. Among transplanted patients, 48 patients completed pretransplant cognitive testing. Better pretransplant cognitive function was associated with lower risk of delirium (odds ratio, 0.69 [95% confidence interval 0.48, 0.99], P = .043); and demographic and clinical features including native disease (P = .236), the Charlson comorbidity index (P = .581), and the lung allocation score (P = .871) were unrelated to risk of delirium, although there was a trend for women to experience delirium less frequently (P = .071). The presence (P = .006) and duration (P = .027) of delirium were both associated with longer hospital stays., Conclusion: Delirium occurs in more than one-third of patients after lung transplantation. Delirium was associated with poorer pretransplant cognitive functioning and longer hospital stays, after accounting for other medical and demographic factors., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Progress for improving outcomes in pediatric patients with solid tumors remains slow. In addition, currently available therapies are fraught with numerous side effects, often causing significant life-long morbidity for long-term survivors. The use of viruses to kill tumor cells based on their increased vulnerability to infection is gaining traction, with several viruses moving through early and advanced phase clinical testing. The prospect of increased efficacy and decreased toxicity with these agents is thus attractive for pediatric cancer. In part I of this two-part review, we focus on strategies for utilizing oncolytic engineered herpes simplex virus (HSV) to target pediatric malignancies. We discuss mechanisms of action, routes of delivery, and the role of preexisting immunity on antitumor efficacy. Challenges to maximizing oncolytic HSV in children are examined, and we highlight how these may be overcome through various arming strategies. We review the preclinical and clinical evidence demonstrating safety of a variety of oncolytic HSVs. In Part II, we focus on the antitumor efficacy of oncolytic HSV in pediatric tumor types, pediatric clinical advances made to date, and future prospects for utilizing HSV in pediatric patients with solid tumors.

Obsessive-compulsive disorder (OCD) in children is a chronic and debilitating disorder. Cognitive theories propose that threat biases may play a role in the development and maintenance of various anxiety disorders, including OCD. Although there is a small body of research examining cognitive theories of OCD in samples of children and youth (e.g., Reynolds & Reeves, 2008), to date, there are no studies that have examined overestimation of threat in children in relation to ambiguous scenarios that may imbue mildly aversive, neutral, and positive interpretations. Children with primary OCD and their mothers ( n = 22 dyads) and nonclinical children and their mothers ( n = 26 dyads) participated in this study. Children with OCD were less accurate in identifying expected feelings across scenarios and perceived all types of situations as being more difficult compared with nonclinical children; however, after controlling for self-reported anxiety symptoms, there were no group differences. Child groups did not differ on other indices of interpretation bias. Mothers of children with OCD, compared with mothers of nonclinical children, also interpreted all types of situations as more threatening and difficult and were less accurate in identifying appropriate emotions in ambiguous situations that may imbue mildly positive connotations. Results are discussed in terms of the broader literature on interpretation bias in anxious children and youth and implications for future research and practice.

Anxious children show attention biases towards and away from threat stimuli. Moreover, threat avoidance compared to vigilance predicts a poorer outcome from exposure-based treatments, such as cognitive-behavioural therapy (CBT), yet the mechanisms underlying this differential response are unclear. Pavlovian fear conditioning is a widely accepted theory to explain the acquisition and extinction of fear, including exposure-based treatments, such as CBT. In typical fear conditioning experiments, anxious children have shown larger physiological responses to an aversive unconditional stimulus (i.e., US on CS+ trials) and to non-reinforced stimuli (CS-) during fear acquisition and to both CSs during fear extinction compared to non-anxious peers. This study examined whether threat avoidance compared to threat vigilance was related to differences in fear acquisition and extinction in anxious children. Thirty-four clinically-anxious children completed a visual probe task including angry-neutral face pairs to determine the direction of threat attention bias as well as a discriminant conditioning and extinction task in which a geometric shape CS+ was paired with an aversive tone US, while the CS- geometric shape was always presented alone during acquisition trials. Both CSs were presented alone during extinction trials. Fear acquisition and extinction were indexed by skin conductance responses (SCR) and subjective measures. Children were classified as threat vigilant (N = 18) and threat avoidant (n = 16) based on the direction of threat attention bias on the visual probe task. During acquisition, threat avoidant relative to threat vigilant anxious children displayed larger orienting SCRs to both CSs during the first block of trials and larger third interval SCRs to the US on CS+ trials as well as on CS- trials. During extinction, threat avoidant anxious children showed delayed extinction of SCRs to both the CS+ and CS- and reported higher subjective anxiety ratings after extinction compared to threat vigilant anxious children. Threat avoidant anxious children may be more reactive physiologically to novel cues and to stimuli that become associated with threat and this may interfere with extinction learning. These findings could help explain previous evidence that threat avoidant anxious children do not respond as well as threat vigilant anxious children to exposure-based CBT., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

Oncolytic engineered herpes simplex viruses (HSVs) possess many biologic and functional attributes that support their use in clinical trials in children with solid tumors. Tumor cells, in an effort to escape regulatory mechanisms that would impair their growth and progression, have removed many mechanisms that would have protected them from virus infection and eventual virus-mediated destruction. Viruses engineered to exploit this weakness, like mutant HSV, can be safely employed as tumor cell killers, since normal cells retain these antiviral strategies. Many preclinical studies and early phase trials in adults demonstrated that oncolytic HSV can be safely used and are highly effective in killing tumor cells that comprise pediatric malignancies, without generating the toxic side effects of nondiscriminatory chemotherapy or radiation therapy. A variety of engineered viruses have been developed and tested in numerous preclinical models of pediatric cancers and initial trials in patients are underway. In Part II of this review series, we examine the preclinical evidence to support the further advancement of oncolytic HSV in the pediatric population. We discuss clinical advances made to date in this emerging era of oncolytic virotherapy.

This study examined the efficacy of combining two promising approaches to treating children's specific phobias, namely attention training and one 3-h session of exposure therapy ('one-session treatment', OST). Attention training towards positive stimuli (ATP) and OST (ATP+OST) was expected to have more positive effects on implicit and explicit cognitive mechanisms and clinical outcome measures than an attention training control (ATC) condition plus OST (ATC+OST). Thirty-seven children (6-17 years) with a specific phobia were randomly assigned to ATP+OST or ATC+OST. In ATP+OST, children completed 160 trials of attention training responding to a probe that always followed the happy face in happy-angry face pairs. In ATC+OST, the probe appeared equally often after angry and happy faces. In the same session, children completed OST targeting their phobic situation/object. Clinical outcomes included clinician, parent and child report measures. Cognitive outcomes were assessed in terms of change in attention bias to happy and angry faces and in danger and coping expectancies. Assessments were completed before and after treatment and three-months later. Compared to ATC+OST, the ATP+OST condition produced (a) significantly greater reductions in children's danger expectancies about their feared situations/object during the OST and at three-month follow-up, and (b) significantly improved attention bias towards positive stimuli at post-treatment, which in turn, predicted a lower level of clinician-rated phobia diagnostic severity three-months after treatment. There were no significant differences between ATP+OST and ATC+OST conditions in clinician, parent, or child-rated clinical outcomes. Training children with phobias to focus on positive stimuli is effective in increasing attention towards positive stimuli and reducing danger expectancy biases. Studies with larger sample sizes and a stronger 'dose' of ATP prior to the OST may reveal promising outcomes on clinical measures for training attention towards positive stimuli., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

Anxiety and depression are prevalent, impairing disorders. High comorbidity has raised questions about how to define and classify them. Structural models emphasise distinctions between "fear" and "distress" disorders while other initiatives propose they be defined by neurobiological indicators that cut across disorders. This study examined startle reflex (SR) modulation in adolescents with principal fear disorders (specific phobia; social phobia) (n=20), distress disorders (unipolar depressive disorders, dysthymia, generalised anxiety disorder; post-traumatic stress disorder) (n=9), and controls (n=29) during (a) baseline conditions, (b) threat context conditions (presence of contraction pads over the biceps muscle), and (c) an explicit threat cue paradigm involving phases that signalled safety from aversive stimuli (early and late stages of safe phases; early stages of danger phases) and phases that signalled immediate danger of an aversive stimulus (late stages of danger phases). Adolescents with principal fear disorders showed larger SRs than other groups throughout safe phases and early stages of danger phases. SRs did not differ between groups during late danger phases. Adolescents with principal distress disorders showed attenuated SRs during baseline and context conditions compared to other groups. Preliminary findings support initiatives to redefine emotional disorders based on neurobiological functioning., (Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.)

Background: The incidence of oropharyngeal cancer is increasing in the developed world. This has led to a large rise in research activity and clinical trials in this area, yet there is no consensus on which outcomes should be measured. As a result, the outcomes measured often differ between trials of comparable interventions, making the combination or comparison of results between trials impossible. Outcomes may also be 'cherry-picked', such that favourable results are reported, and less favourable results withheld. The development of a minimum outcome reporting standard, known as a core outcome set, goes some way to addressing these problems. Core outcome sets are ideally developed using a patient-centred approach so that the outcomes measured are relevant to patients and clinical practice. Core outcome sets drive up the quality and relevance of research by ensuring that the right outcomes are consistently measured and reported in trials in specific areas of health or healthcare., Methods/design: This is a mixed methods study involving three phases to develop a core outcome set for oropharyngeal cancer clinical trials. Firstly, a systematic review will establish which outcomes are measured in published oropharyngeal cancer randomised controlled trials (RCTs). Secondly, qualitative interviews with patients and carers in the UK and the USA will aim to establish which outcomes are important to these stakeholders. Data from these first two stages will be used to develop a comprehensive list of outcomes to be considered for inclusion in the core outcome set. In the third stage, patients and clinicians will participate in an iterative consensus exercise known as a Delphi study to refine the contents of the core outcome set. This protocol lays out the methodology to be implemented in the CONSENSUS study., Discussion: A core outcome set defines a minimum outcome reporting standard for clinical trials in a particular area of health or healthcare. Its consistent implementation in oropharyngeal cancer clinical trials will improve the quality and relevance of research., Trials and Registration: This study is registered at the National Institute for Health Research (NIHR) Clinical Research Network (CRN) portfolio, ID 13823 (17 January 2013).

Elevated responding to safety cues in the context of threat is associated with anxiety disorder onset, but pathways underlying such responding remain unclear. This study examined whether childhood/adolescent adversity was associated with larger startle reflexes during safe phases of a fear potentiation startle paradigm (following delivery of an aversive stimulus) that predict anxiety disorders. Participants (N = 104) came from the Youth Emotion Project, a longitudinal study of risk factors for emotional disorders. Participants with no baseline psychopathology underwent a startle modulation protocol and were assessed for childhood and adolescent adversities using a validated interview. Adolescent adversity was associated with larger startle reflexes during the safe phases following an aversive stimulus. Neither child nor adolescent adversities were associated with responding during any other phase of the protocol. These findings suggest a pathway between adolescent adversity and a risk factor for anxiety disorders wherein adolescent adversity contributes to impaired responding to safety cues.

Background: Structural models of emotional disorders propose that anxiety disorders can be classified into fear and distress disorders. Sources of evidence for this distinction come from genetic, self-report and neurophysiological data from adults. The present study examined whether this distinction relates to cognitive processes, indexed by attention bias towards threat, which is thought to cause and maintain anxiety disorders., Method: Diagnostic and attention bias data were analysed from 435 children between 5 and 13 years of age; 158 had principal fear disorder (specific phobia, social phobia or separation anxiety disorder), 75 had principal distress disorder (generalized anxiety disorder, GAD) and 202 had no psychiatric disorder. Anxious children were a clinic-based treatment-seeking sample. Attention bias was assessed on a visual-probe task with angry, neutral and happy faces., Results: Compared to healthy controls, children with principal distress disorder (GAD) showed a significant bias towards threat relative to neutral faces whereas children with principal fear disorder showed an attention bias away from threat relative to neutral faces. Overall, children displayed an attention bias towards happy faces, irrespective of diagnostic group., Conclusions: Our findings support the distinction between fear and distress disorders, and extend empirically derived structural models of emotional disorders to threat processing in childhood, when many anxiety disorders begin and predict lifetime impairment.

Purpose: To determine normal retinal oxygen saturation (SO2) values measured with retinal oximetry in a multiethnic group of healthy subjects and to evaluate the association of retinal SO2 with demographic and clinical parameters., Methods: Retinal oximetry was performed in both eyes of 61 normal healthy subjects. Global and quadrant venous (SvO2) and arterial oxygen saturation (SaO2), arteriovenous difference in SO2, and venular and arteriolar width were measured. The association of SO2 parameters with age, gender, ethnicity, refraction, iris color, history of controlled systemic hypertension, and smoking was analyzed., Results: Average SvO2 and SaO2 were 55.3 ± 7.1% and 90.4 ± 4.3%, respectively. All average measurements were comparable in both eyes, both genders, and among ethnic groups. Inferonasal quadrant SaO2 was higher in Asians. Age was associated with decreased SvO2 (β = -0.19; P = 0.001) and SaO2 (β = -0.11; P = 0.003). History of controlled systemic hypertension was associated with an increase in arteriovenous difference in SO2 (β = 3.99; P = 0.013)., Conclusion: This is the first description of retinal SO2 in healthy, multiethnic subjects. Aging decreases SvO2 and SaO2 and should be accounted for when interpreting retinal oximetry measurements. Other demographic and clinical parameters studied did not seem to significantly influence retinal SO2 measurements.

Recently, investigators showed that mice with syngeneic murine gliomas that were treated with a neuroattenuated oncolytic herpes simplex virus-1 (oHSV), M002, had a significant increase in survival. M002 has deletions in both copies of the γ134.5 gene, enabling replication in tumor cells but precluding infection of normal cells. Previous studies have shown antitumor effects of other oHSV against a number of adult tumors including hepatocellular carcinoma and renal cell carcinoma. The purpose of the current study was to investigate the oncolytic potential of M002 against difficult to treat pediatric liver and kidney tumors. We showed that the oHSV, M002, infected, replicated, and decreased cell survival in hepatoblastoma, malignant rhabdoid kidney tumor, and renal sarcoma cell lines. In addition, we showed that in murine xenografts, treatment with M002 significantly increased survival and decreased tumor growth. Finally, these studies showed that the primary entry protein for oHSV, CD111 (nectin-1) was present in human hepatoblastoma and malignant rhabdoid kidney tumor specimens. We concluded that M002 effectively targeted these rare aggressive tumor types and that M002 may have potential for use in children with unresponsive or relapsed pediatric solid tumors.

Maternal anxiety and depression are significant risk factors for the development of these disorders in offspring. The pathways through which risk is conferred remain unclear. This study examined fear acquisition and extinction in 26 children at high risk for emotional disorders by virtue of maternal psychopathology (n=14 with a mother with a principal anxiety disorder and n=12 with a mother with a principal unipolar depressive disorder) and 31 low risk controls using a discriminative Pavlovian conditioning procedure. Participants, aged between 7 and 14 years, completed 16 trials of discriminative conditioning of two geometric figures, with (CS+) and without (CS-) an aversive tone (US), followed by 8 extinction trials (4×CS+, 4×CS-). In the context of comparable discriminative conditioning, children of anxious mothers showed larger skin conductance responses during extinction to the CS+ compared to the CS-, and to both CSs from the first to the second block of extinction trials, in comparison with low risk controls. Compared to low risk controls, children of depressed mothers showed smaller skin conductance responses to the CS+ than the CS- during acquisition. These findings suggest distinct psychophysiological premorbid risk markers in offspring of anxious and depressed mothers., (Copyright © 2013 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Neuroblastoma tumorigenesis and malignant transformation is driven by overexpression and dominance of cell survival pathways and a lack of normal cellular senescence or apoptosis. Therefore, manipulation of cell survival pathways may decrease the malignant potential of these tumors and provide avenues for the development of novel therapeutics. This review focuses on the individual protein tyrosine kinase, focal adhesion kinase (FAK) and its interaction with the transcription factors, MYCN, p53, and Mdm2, and how their interactions modulate the growth and malignancy of neuroblastomas.

Despite intensive research efforts and therapeutic advances over the last few decades, the pediatric neural crest tumor, neuroblastoma, continues to be responsible for over 15% of pediatric cancer deaths. Novel therapeutic options are needed for this tumor. Recently, investigators have shown that mice with syngeneic murine gliomas treated with an engineered, neuroattenuated oncolytic herpes simplex virus-1 (oHSV), M002, had a significant increase in survival. M002 has deletions in both copies of the γ 1 34.5 gene, enabling replication in tumor cells but precluding infection of normal neural cells. We hypothesized that M002 would also be effective in the neural crest tumor, neuroblastoma. We showed that M002 infected, replicated, and decreased survival in neuroblastoma cell lines. In addition, we showed that in murine xenografts, treatment with M002 significantly decreased tumor growth, and that this effect was augmented with the addition of ionizing radiation. Importantly, survival could be increased by subsequent doses of radiation without re-dosing of the virus. Finally, these studies showed that the primary entry protein for oHSV, CD111 was expressed by numerous neuroblastoma cell lines and was also present in human neuroblastoma specimens. We concluded that M002 effectively targeted neuroblastoma and that this oHSV may have potential for use in children with unresponsive or relapsed neuroblastoma.

Background: This study examined the feasibility and preliminary effectiveness of d-cycloserine (DCS)-augmented cognitive behavioral therapy (CBT) for children and adolescents with difficult-to-treat Obsessive Compulsive Disorder, in a double-blind randomized controlled pilot trial (RCT)., Methods: Seventeen children and adolescents (aged 8-18 years) with a primary diagnosis of OCD, which was deemed difficult-to-treat, were randomly assigned to either nine sessions of CBT including five sessions of DCS-augmented exposure and response prevention (ERP) [ERP + DCS] or nine sessions of CBT including five sessions of placebo-augmented ERP [ERP + PBO]. Weight-dependent DCS or placebo doses (25 or 50 mg) were taken 1 hour before ERP sessions., Results: At posttreatment, both groups showed significant improvements with 94% of the entire sample classified as responders. However, a greater improvement in the ERP + DCS relative to the ERP + PBO condition was observed at 1-month follow-up on clinician-rated obsessional severity and diagnostic severity, and parent ratings of OCD severity. There were no changes across time or condition from 1- to 3-month follow-up., Conclusions: In this preliminary study, DCS-augmented ERP produced significant improvements in OCD severity from posttreatment to 1-month follow-up, relative to a placebo control condition, in severe and difficult-to-treat pediatric OCD. The significant effect on obsessional severity suggests that DCS augmentation might be associated with enhanced modification of obsessional thoughts during ERP, and warrants further investigation., (© 2013 Wiley Periodicals, Inc.)

The results presented herein summarize the most up-to-date cardiovascular statistics available at this time in Australia. The analysis presented here is based on and extends results published in two Australian Institute of Health and Welfare (AIHW) reports, namely Cardiovascular disease: Australian facts 2011 and the cardiovascular disease (CVD) section of Australia's Health 2012. Despite significant improvements in the cardiovascular health of Australians in recent decades, CVD continues to impose a heavy burden on Australians in terms of illness, disability and premature death. Direct health care expenditure for CVD exceeds that for any other disease group. The most recent national data have been analysed to describe patterns and trends in CVD hospitalization and death rates, with additional analysis by Indigenous status, remoteness and socioeconomic group. The incidence of and case-fatality from major coronary events has also been examined. Although CVD death rates have declined steadily in Australia since the late 1960s, CVD still accounts for a larger proportion of deaths (33% in 2009) than any other disease group. Worryingly, the rate at which the coronary heart disease death rate has been falling in recent years has slowed in younger (35-54 years) age groups. Between 1998-99 and 2009-10, the overall rate of hospitalizations for CVD fell by 13%, with declines observed for most major CVDs. In conclusion, CVD disease remains a significant health problem in Australia despite decreasing death and hospitalization rates., (© 2013 The Authors Clinical and Experimental Pharmacology and Physiology © 2013 Wiley Publishing Asia Pty Ltd.)

Objective: Attention bias modification training (ABMT) is a promising treatment. Nevertheless, few studies examine its effectiveness in anxious children. This study examined the efficacy of such an ABMT protocol in pediatric anxiety., Method: 37 anxious children were randomly assigned to one of two ABMT conditions. In the attention-towards-positive (ATP) condition, children searched 3×3 matrices for a happy face amongst angry faces. In the attention-training-control (ATC) condition, they searched for a bird amongst flowers. Children completed 160 trials in each of four training sessions per week for three weeks at home (1920 total trials). Clinical and attention bias measures were assessed before and after ABMT., Results: Children randomized to ATP showed greater post-training attention bias towards happy faces than children randomized to ATC. ATP also produced significantly greater reductions in clinician-rated diagnostic severity and number of diagnoses, compared to ATC. In the ATP group, 50% of children who completed training did not meet criteria for their principal diagnosis, compared to 8% in the ATC group., Conclusion: Training anxious children to focus attention on positive features of their environment may be a promising treatment., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

This study examined the incidence and correlates of functional gastrointestinal symptoms in children with anxiety disorders. Participants were 6-13 year old children diagnosed with one or more anxiety disorders (n = 54) and non-clinical control children (n = 51). Telephone diagnostic interviews were performed with parents to determine the presence and absence of anxiety disorders in children. Parents completed a questionnaire that elicited information about their child's gastrointestinal symptoms associated with functional gastrointestinal disorders in children, as specified by the paediatric Rome criteria (Caplan et al., Journal of Pediatric Gastroenterology & Nutrition, 41, 296-304, 2005a). Parents and children also completed a symptom severity measure of anxiety. As expected, children with anxiety disorders were significantly more likely to have symptoms of functional gastrointestinal disorders (FGID), compared to children without anxiety disorders. That is, 40.7 % of anxious children had symptoms of a FGID compared to 5.9 % of non-anxious control children. Children with anxiety disorders were significantly more likely to have symptoms of functional constipation, and showed a trend for a higher incidence of irritable bowel syndrome symptoms compared to non-anxious control children. Furthermore, higher anxiety symptom severity was characteristic of anxious children with symptoms of FGID, compared to anxious children without FGID symptoms and non-anxious control children. Also, children with anxiety disorders, regardless of FGID symptoms, were more likely to have a biological family member, particularly a parent or grandparent, with a gastrointestinal problem, compared to non-anxious control children. The high incidence of FGID symptoms in children with anxiety disorders warrants further research on whether gastrointestinal symptoms reduce following psychological treatments for childhood anxiety disorders, such as cognitive behavioural therapy.

Background: Because annulated indoles have almost no representation in the PubChem or MLSMR databases, an unprecedented class of an indole-based library was constructed, using the indole aryne methodology, and screened for antitumor activity. Sixty-six novel 6,7-annulated-4-substituted indole compounds were synthesized, using a strategic combination of 6,7-indolyne cycloaddition and cross-coupling reactions under both Suzuki-Miyaura and Buchwald-Hartwig conditions, and tested for their effectiveness against murine L1210 tumor cell proliferation in vitro., Materials and Methods: Various markers of tumor cell metabolism, DNA degradation, mitotic disruption, cytokinesis and apoptosis were assayed in vitro to evaluate drug cytotoxicity., Results: Most compounds inhibited the metabolic activity of leukemic cells in a time- and concentration-dependent manner but only 9 of them were sufficiently potent to inhibit L1210 tumor cell proliferation by 50% in the low-μM range after 2 (IC(50): 4.5-20.4 μM) and 4 days (0.5-4.0 μM) in culture. However, the antiproliferative compounds that were the most effective at day 4 were not necessarily the most potent at day 2, suggesting different speeds of action. A 3-h treatment with antiproliferative annulated indole was sufficient to inhibit, in a concentration-dependent manner, the rate of DNA synthesis measured in L1210 cells over a 0.5-h period of pulse-labeling with (3)H-thymidine. Four of the antiproliferative compounds had weak DNA-binding activities but one compound reduced the fluorescence of the ethidium bromide-DNA complex by up to 53%, suggesting that some annulated indoles might directly interact with double-stranded DNA to disrupt its integrity and prevent the dye from intercalating into DNA base pairs. However, all 9 antiproliferative compounds induced DNA cleavage at 24 h in L1210 cells, containing (3)H-thymidine-prelabeled DNA, suggesting that these antitumor annulated indoles might trigger an apoptotic pathway of DNA fragmentation. Indeed the antiproliferative annulated indoles caused a time-dependent increase of caspase-3 activity with a peak at 6 h. Interestingly, the compounds with the most potent antiproliferative IC(50) values at day 2 were consistently the most effective at inhibiting DNA synthesis at 3 h and inducing DNA fragmentation at 24 h. After 24-48 h, antiproliferative concentrations of annulated indoles increased the mitotic index of L1210 cells and stimulated the formation of many bi-nucleated cells, multi-nucleated cells, apoptotic cells and micronuclei, suggesting that these antitumor compounds might enhance mitotic abnormality, induce chromosomal damage or missegregation, and block cytokinesis to induce apoptosis., Conclusion: Although annulated indoles may have interesting bioactivity, novel derivatives with different substitutions must be synthesized to elucidate structure-activity relationships, identify more potent antitumor lead compounds, and investigate their molecular targets and mechanisms of action.

A considerable body of research has identified various child and parent factors that contribute to and maintain anxiety symptoms in children. Yet relatively few studies have examined child factors (including threat-based cognitive bias, neuroticism, gender, puberty and age) as well as parent factors (including maternal anxiety and child-rearing style) in association with child anxiety symptoms, and the extent to which these factors serve as unique predictors of child anxiety. Moreover, research is lacking on whether parent factors such as child-rearing style, which is often targeted in early intervention and treatment programs, might mediate the association between child factors such as neuroticism, and child anxiety symptoms. In a sample of 85 children between 7 and 12 years of age with varying levels of anxiety, including those with diagnosed anxiety disorders, results showed that children were more anxious when they were reported to be more advanced in pubertal status by their parents, when they had a tendency to interpret more threat in ambiguous situations, and when they self-reported more neuroticism. Regarding parent factors, maternal self-reported trait anxiety and children's perceptions of their mother as having an anxious child-rearing style were associated with higher levels of child anxiety. Moreover, when these correlates of child anxiety were examined in a multivariate model to identify those that had direct as well as indirect associations via maternal anxious child-rearing style, child neuroticism remained as a significant and unique predictor of child anxiety that was also mediated by maternal anxious-rearing. Child neuroticism also mediated the relationship between child pubertal stage and anxiety symptoms. Results are discussed in terms of relevant theory and empirical evidence regarding the roles of both child and parent factors in the development of child anxiety., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

Objective: Multiple cognitive biases associated with adult obsessive-compulsive disorder (OCD) were tested in a clinical sample of children (ages 7-11) and adolescents (12-17) and their mothers. This study examined (a) the associations between child cognitive biases and OCD severity, (b) maternal cognitive biases and child OCD severity, and (c) maternal cognitive bias and child cognitive bias. It was hypothesized that age would significantly moderate these relationships, with stronger associations with OCD severity for cognitive bias in adolescents (relative to children), and maternal cognitive bias in younger children (relative to adolescents)., Method: Forty-six children and adolescents diagnosed with OCD and their mothers completed questionnaires assessing responsibility bias, thought-action fusion (TAF), thought suppression, and metacognitive beliefs. OCD symptoms were assessed using structured diagnostic interviews and semistructured symptom interviews., Results: As predicted, age significantly moderated associations between (a) child cognitive variables and OCD severity-specifically between child responsibility and child metacognition, which were associated with OCD severity for adolescents only; (b) maternal cognitive biases and child OCD severity-specifically for maternal responsibility and thought suppression, which were significantly and positively associated with child OCD severity but not adolescent OCD severity; and (c) maternal cognitive biases and child cognitive bias-such that significant associations were evident only in the younger child sample, and only between maternal TAF self and metacognition, with child suppression and child TAF moral, respectively., Conclusion: Maternal cognitive biases are more consistently linked to greater OCD severity among younger children, whereas personal cognitive biases are associated with greater OCD symptoms in adolescents. Treatments for pediatric OCD are likely to be improved by age-specific considerations for the role of maternal and child cognitive biases associated with OCD., (Copyright © 2011. Published by Elsevier Ltd.)

Background: Members of two seemingly unrelated kindreds of Arab Moslem origin presented with pronounced early onset spastic paraparesis of upper and lower limbs, mild intellectual disability, kyphosis, pectus carinatum and hypertrichosis., Methods: The authors performed neurological and developmental examinations on the affected individuals. The authors conducted whole genome linkage and haplotype analyses, followed by sequencing of candidate genes; RNA and protein expression studies; and finally proof of principle investigations on knockdown morpholino oligonucleotide injected zebrafish., Results: The authors characterise a novel form of autosomal recessive complex hereditary spastic paraparesis (CHSP). MRI studies of brain and spinal cord were normal. Within a single significantly linked locus the authors ultimately identified a homozygous missense mutation c.1146A>T (p.K382N) in the vacuolar protein sorting 37A (Vps37A) gene, fully penetrant and segregating with the disease in both families. Mobility was significantly reduced in Vps37A knockdown morpholino oligonucleotide injected zebrafish, supporting the causal relationship between mutations in this gene and the phenotype described in the patients of this study., Conclusions: The authors provide evidence for the involvement of Vps37A, a member of the endosomal sorting complex required for transport (ESCRT) system, in upper motor neuron disease. The ESCRT system has been shown to play a central role in intracellular trafficking, in the maturation of multivesicular bodies and the sorting of ubiquitinated membrane proteins into internal luminal vesicles. Further investigation of mechanisms by which dysfunction of this gene causes CHSP will contribute to the understanding of intracellular trafficking of vesicles by the ESCRT machinery and its relevance to CHSP.

Background: A bias to selectively direct attention to threat stimuli is a cognitive characteristic of anxiety disorders. Recent studies indicate that individual differences in pre-treatment threat attention bias predict treatment outcomes from cognitive-behavioural therapy (CBT) in anxious individuals. However, there have been inconsistent findings regarding whether attention bias towards threat predicts better or poorer treatment outcome., Method: This longitudinal study examined treatment outcomes in 35 clinically-anxious children following a 10-week, group-based CBT program, as a function of whether children showed a pre-treatment attention bias towards or away from threat stimuli. The effect of CBT on attention bias was also assessed., Results: Both groups showed significant improvement after receiving CBT. However, anxious children with a pre-treatment attention bias towards threat showed greater reductions not only in anxiety symptom severity, but also in the likelihood of meeting diagnostic criteria for anxiety disorders at post-treatment assessment, in comparison with anxious children who showed a pre-treatment attention bias away from threat. Children who had a pre-treatment bias away from threat showed a reduction in this bias over the course of CBT., Conclusions: Findings suggest that pre-existing differences in the direction of attention towards versus away from threat could have important implications for the treatment of anxious children., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

The current study evaluated the degree to which startle reflexes (SRs) in safe conditions versus danger conditions were predictive of the onset of anxiety disorders. Specificity of these effects to anxiety disorders was evaluated in comparison to unipolar depressive disorders and with consideration of level of neuroticism. A startle paradigm was administered at baseline to 132 nondisordered adolescents as part of a longitudinal study examining risk factors for emotional disorders. Participants underwent a repetition of eight safe-danger sequences and were told that delivery of an aversive stimulus leading to a muscle contraction of the arm would occur only in the late part of danger conditions. One aversive stimulus occurred midway in the safe-danger sequences. Participants were assessed for the onset of anxiety and unipolar depressive disorders annually over the next 3 to 4 years. Larger SR magnitude during safe conditions following delivery of the aversive stimulus predicted the subsequent first onset of anxiety disorders. Moreover, prediction of the onset of anxiety disorders remained significant above and beyond the effects of comorbid unipolar depression, neuroticism, and subjective ratings of intensity of the aversive stimulus. In sum, elevated responding to safe conditions following an aversive stimulus appears to be a specific, prospective risk factor for the first onset of anxiety disorders.

Inactivating mutations in phosphate-regulating endopeptidase (PHEX) cause X-linked hypophosphatemic rickets (XLHR) characterized by phosphaturia, hypophosphatemia, bony deformities, and growth retardation. We assessed the efficacy of combined calcitriol and orally administered phosphate (Pi) therapy on longitudinal growth in relation to age at treatment onset in a retrospective, single-center review of children with XLHR and documented PHEX mutations. Growth was compared in those who started treatment before (G1; N = 10; six boys) and after (G2; N = 13; five boys) 1 year old. Median height standard deviation score (HSDS) at treatment onset was normal in G1: 0.1 [interquartile range (IR) -1.3 to 0.4) and significantly (p = 0.004) lower in G2 (IR -2.1 (-2.8 to -1.4). Treatment duration was similar [G1 8.5 (4.0-15.2) vs G2 11.9 (6.2-14.3) years; p = 0.56], as were prescribed phosphate and calcitriol doses. Recent HSDS was significantly (p = 0.009) better in G1 [-0.7 (-1.5 to 0.3)] vs G2 [-2.0 (-2.3 to -1.0)]. No effects of gender or genotype on growth could be identified. Children with PHEX-associated XLHR benefit from early treatment and can achieve normal growth. Minimal catchup growth was seen in those who started treatment later. Our findings emphasize the importance of early diagnosis to allow treatment before growth has been compromised.

Background/aim: The ageing population in Australia may contribute to an epidemic of stroke in coming years. We aimed to assess whether deaths and hospitalisations from stroke in Australia are increasing., Methods: Nationwide age- and sex-specific hospitalisation episode data from 1996 to 1997 were used to predict future hospitalisations from stroke. Age- and sex-specific mortality data from 1997 were used to predict future mortality from stroke. These predictions were based on an expected increase in the population's age and population growth. We compared these estimates to those observed in national figures for the following 9 years., Results: Based on 1996-1997 hospitalisation rates, we calculated that hospitalisations for stroke would be expected to rise from 27,399 to 35,041 in 2005-2006. Using 1997 mortality rates, deaths from stroke would be expected to rise from 9,126 to 12,726 in 2007. Observed hospitalisations (2005-2006) were 6,380 fewer than expected, while deaths (2007) were 4,103 fewer than expected. This represents a 2.21% annual reduction in hospitalisation rate, and a 4.0% annual reduction in mortality rate., Conclusion: Encouragingly, hospitalisation and mortality rates for stroke appear to be declining. If these figures reflect actual occurrences of stroke then it may be that primary and secondary prevention strategies are working., (Copyright © 2012 S. Karger AG, Basel.)

Notch signaling in podocytes causes proteinuria and glomerulosclerosis in humans and rodents, but the underlying mechanism remains unknown. Here, we analyzed morphologic, molecular, and cellular events before the onset of proteinuria in newborn transgenic mice that express activated Notch in podocytes. Immunohistochemistry revealed a loss of the slit diaphragm protein nephrin exclusively in podocytes expressing activated Notch. Podocyte-specific deletion of Rbpj, which is essential for canonical Notch signaling, prevented this loss of nephrin. Overexpression of activated Notch decreased cell surface nephrin and increased cytoplasmic nephrin in transfected HEK293T cells; pharmacologic inhibition of dynamin, but not depletion of cholesterol, blocked these effects on nephrin, suggesting that Notch promotes dynamin-dependent, raft-independent endocytosis of nephrin. Supporting an association between Notch signaling and nephrin trafficking, electron microscopy revealed shortened podocyte foot processes and fewer slit diaphragms among the transgenic mice compared with controls. These data suggest that Notch signaling induces endocytosis of nephrin, thereby triggering the onset of proteinuria.

Many studies have reported concurrent relationships between depressive symptoms and various personality, cognitive, and personality-cognitive vulnerabilities, but the degree of overlap among these vulnerabilities is unclear. Moreover, whereas most investigations of these vulnerabilities have focused on depression, their possible relationships with anxiety have not been adequately examined. The present study included 550 high school juniors and examined the cross-sectional relationships among neuroticism, negative inferential style, dysfunctional attitudes, sociotropy, and autonomy, with a wide range of anxiety and depressive symptoms, as well as the incremental validity of these different putative vulnerabilities when examined simultaneously. Correlational analyses revealed that all five vulnerabilities were significantly related to symptoms of both anxiety and depression. Whereas neuroticism accounted for significant unique variance in all symptom outcomes, individual cognitive and personality-cognitive vulnerabilities accounted for small and only sometimes statistically significant variance across outcomes. Importantly, however, for most outcomes the majority of symptom variance was accounted for by shared aspects of the vulnerabilities rather than unique aspects. Implications of these results for understanding cognitive and personality-cognitive vulnerabilities to depression and anxiety are discussed.

Ciliopathies comprise a group of disorders associated with genetic mutations encoding defective proteins, which result in either abnormal formation or function of cilia. As cilia are a component of almost all vertebrate cells, cilia dysfunction can manifest as a constellation of features that include characteristically, retinal degeneration, renal disease and cerebral anomalies. Additional manifestations include congenital fibrocystic diseases of the liver, diabetes, obesity and skeletal dysplasias. Ciliopathic features have been associated with mutations in over 40 genes to date. However, with over 1,000 polypeptides currently identified within the ciliary proteome, several other disorders associated with this constellation of clinical features will likely be ascribed to mutations in other ciliary genes. The mechanisms underlying many of the disease phenotypes associated with ciliary dysfunction have yet to be fully elucidated. Several elegant studies have crucially demonstrated the dynamic ciliary localisation of components of the Hedgehog and Wnt signalling pathways during signal transduction. Given the critical role of the cilium in transducing "outside-in" signals, it is not surprising therefore, that the disease phenotypes consequent to ciliary dysfunction are a manifestation of aberrant signal transduction. Further investigation is now needed to explore the developmental and physiological roles of aberrant signal transduction in the manifestation of ciliopathy phenotypes. Utilisation of conditional and inducible murine models to delete or overexpress individual ciliary genes in a spatiotemporal and organ/cell-specific manner should help clarify some of the functional roles of ciliary proteins in the manifestation of phenotypic features.

Background: Because quinazolines and their derivatives exhibit a wide range of pharmacological profiles, there is a continuous interest among synthetic and medicinal chemists in the discovery of more potent analogs. Ten novel quinazoliniminium salts were synthesized and tested for their effectiveness against murine and human tumor cell proliferation in vitro., Materials and Methods: Various markers of tumor cell metabolism, DNA degradation and mitotic disruption were assayed in vitro to evaluate drug cytotoxicity., Results: All compounds induced concentration- and time-dependent antitumor effects in vitro but the 2-chloro-3-(4-methoxyphenyl)quinazolin-4(3H)-iminium chloride (4) was the most effective inhibitor of leukemia L1210 cell proliferation at days 2-4 (IC50: 2.1-0.9 μM), suggesting that the para-methoxyphenyl substituent on the N3 of 4 may enhance the antiproliferative properties of the quinazoliniminium scaffold. In mammary SK-BR-3 tumor cells, 4 reduced the Ki-67 marker of cell proliferation at 24 h and the metabolic activity at days 2 and 4. Moreover, a 1.5- or 3-h treatment with 4 was sufficient to inhibit the rates of DNA, RNA and protein syntheses measured in L1210 cells over 0.5- or 1-h periods of pulse-labeling with 3H-thymidine, 3H-uridine and 3H-leucine, respectively. As 4 did not reduce the fluorescence of the ethidium bromide-DNA complex, this compound was unlikely to directly bind to or destabilize double-stranded DNA. However, 4 induced DNA cleavage at 24 h in L1210 cells containing 3H-thymidine-prelabeled DNA, suggesting that this antitumor drug might trigger an apoptotic pathway of DNA fragmentation. After 12-48 h, 4 weakly increased the mitotic index of L1210 cells but stimulated the formation of many binucleated cells, multinucleated cells and micronuclei, suggesting that this antitumor compound might enhance mitotic abnormality, induce chromosomal damage or missegregation, and block cytokinesis., Conclusion: Although 4 may have interesting bioactivity, more compounds based on the quinazoliniminium scaffold must be synthesized to elucidate structure-activity relationships, identify more potent antitumor lead compounds, and investigate their molecular targets and mechanisms of action.

Atypical hemolytic uremic syndrome (aHUS) is a heterogeneous disease that is caused by defective complement regulation in over 50% of cases. Mutations have been identified in genes encoding both complement regulators [complement factor H (CFH), complement factor I (CFI), complement factor H-related proteins (CFHR), and membrane cofactor protein (MCP)], as well as complement activators [complement factor B (CFB) and C3]. More recently, mutations have also been identified in thrombomodulin (THBD), an anticoagulant glycoprotein that plays a role in the inactivation of C3a and C5a. Inhibitory autoantibodies to CFH account for an additional 5-10% of cases and can occur in isolation or in association with mutations in CFH, CFI, CFHR 1, 3, 4, and MCP. Plasma therapies are considered the mainstay of therapy in aHUS secondary to defective complement regulation and may be administered as plasma infusions or plasma exchange. However, in certain cases, despite initiation of plasma therapy, renal function continues to deteriorate with progression to end-stage renal disease and renal transplantation. Recently, eculizumab, a humanized monoclonal antibody against C5, has been described as an effective therapeutic strategy in the management of refractory aHUS that has failed to respond to plasma therapy. Clinical trials are now underway to further evaluate the efficacy of eculizumab in the management of both plasma-sensitive and plasma-resistant aHUS.

Background: We have reported that a scheduled nonnarcotic analgesic regimen after dorsal lumbar rhizotomy and Chiari I malformation decompression is efficacious in managing postoperative pain in children. To date, this regimen has not been analyzed in children after brain tumor biopsy or resection., Objective: To elucidate the safety and utility of such an analgesic protocol in these patients., Patients and Methods: A database review was conducted to identify children who received a scheduled dose of alternating acetaminophen and ibuprofen after craniotomy for tumor biopsy or resection, and postoperative imaging was evaluated., Results: Fifty-one children who met the inclusion criteria were identified. On postoperative imaging, 17.67% had routine, postoperative blood in the resection cavity according to both radiology and neurosurgical review. One patient had moderate postoperative bleeding in the tumor cavity. Overall, 44 of the 51 patients (86.3%) required no or minimal narcotic medication for pain., Conclusion: A scheduled regimen of nonsteroidal antiinflammatory drugs given in alternating doses immediately after craniotomy for tumor biopsy or resection and throughout hospitalization did not result in any significant postoperative hemorrhage in our patient series.

A series of 1,4-diaryl tetrazol-5-ones were synthesized by copper mediated N-arylation of 1-phenyl-1H-tetrazol-5(4H)-one with aryl boronic acids, o-R(1)C(6)H(4)B(OH)(2) where R(1)=H, OMe, Cl, CF(3), Br, CCH. The 1,4-diaryl tetrazol-5-ones substituted with OMe, Cl, CF(3), Br underwent thionation with Lawesson's reagent to yield the corresponding 5-thio derivatives. The 1-(2-bromophenyl)-4-phenyl-1H-tetrazole-5(4H)-thione so obtained was subjected to lithiation/protonation and Sonogashira coupling to produce 1,4-diphenyl-1H-tetrazole-5(4H)-thione and 1-(2-ethynylphenyl)-4-phenyl tetrazole-5-thione, respectively. The title compounds were found to be stable to strong Lewis acid conditions. Three of these novel compounds were found to inhibit L1210 leukemia cell proliferation and SK-BR-3 breast cancer cell growth over several days in culture in vitro. Shorter tetrazole derivative treatments also reduced the expression of the Ki-67 marker of cell proliferation in SK-BR-3 cells and the rate of DNA synthesis in L1210 cells., (2010 Elsevier Ltd. All rights reserved.)

Background: Several theories have posited a common internalizing factor to help account for the relationship between mood and anxiety disorders. These disorders are often co-morbid and strongly covary. Other theories and data suggest that personality traits may account, at least in part, for co-morbidity between depression and anxiety. The present study examined the relationship between neuroticism and an internalizing dimension common to mood and anxiety disorders., Method: A sample of ethnically diverse adolescents (n=621) completed self-report and peer-report measures of neuroticism. Participants also completed the Structured Clinical Interview for DSM-IV (SCID)., Results: Structural equation modeling showed that a single internalizing factor was common to lifetime diagnosis of mood and anxiety disorders, and this internalizing factor was strongly correlated with neuroticism. Neuroticism had a stronger correlation with an internalizing factor (r=0.98) than with a substance use factor (r=0.29). Therefore, neuroticism showed both convergent and discriminant validity., Conclusions: These results provide further evidence that neuroticism is a necessary factor in structural theories of mood and anxiety disorders. In this study, the correlation between internalizing psychopathology and neuroticism approached 1.0, suggesting that neuroticism may be the core of internalizing psychopathology. Future studies are needed to examine this possibility in other populations, and to replicate our findings.

Objective: To examine attentional bias towards angry and happy faces in 8-12 year old children with anxiety disorders (n=29) and non-anxious controls (n=24)., Method: Children completed a visual-probe task in which pairs of angry/neutral and happy/neutral faces were displayed for 500ms and were replaced by a visual probe in the spatial location of one of the faces., Results: Children with more severe anxiety showed an attentional bias towards angry relative to neutral faces, compared with anxious children who had milder anxiety and non-anxious control children, both of whom did not show an attentional bias for angry faces. Unexpectedly, all groups showed an attentional bias towards happy faces relative to neutral ones., Conclusions: Anxiety symptom severity increases attention to threat stimuli in anxious children. This association may be due to differing threat appraisal processes or emotion regulation strategies.

Neuroticism has been hypothesized to be a non-specific risk factor for both anxiety and unipolar mood disorders whereas some cognitive and personality-cognitive vulnerabilities have been hypothesized to be more specific to depression. Using a retrospective design with a sample of 575 high school juniors, we tested three competing models of the associations among these variables. Both neuroticism and the cognitive and personality-cognitive vulnerabilities had significant zero-order associations with rates of past diagnoses of both anxiety and unipolar mood disorders. Neuroticism had significant unique associations with past anxiety disorders and comorbid anxiety and unipolar mood disorders whereas the other vulnerabilities did not. In addition, gender interacted with neuroticism but not with the other vulnerabilities in associating with past diagnoses of mood disorders, showing that neuroticism is more highly associated with past unipolar mood diagnoses in males than in females. Finally, the cognitive and personality-cognitive vulnerabilities overlapped with substantial portions of the variance that neuroticism shared with diagnoses. These results suggest that, at least for retrospective associations with past anxiety and unipolar mood disorders, the cognitive and other personality-cognitive vulnerabilities are non-specific facets of neuroticism., (Copyright 2009 Elsevier Ltd. All rights reserved.)

We used social relations modeling (SRM; mixed modeling and SOREMO) to examine liking among peers (affective preferences) in relation to gender and socioemotional problems. Participants (N=278, age 10 to 13) rated how much they liked each other and reported depressive symptoms, negative beliefs, and social worries. Boys and girls were equally liked, but liked same-gender more than cross-gender peers. Genders showed similar consensus about liking for same-gender peers; rater differences were important for cross-gender liking. Depressed preadolescents were liked less but did not like classmates less. Participants who attributed more negative qualities to peers were less liked and liked others less. SRM showed no associations between worry and affective preferences, whereas others analyses indicated those with high worry were less liked. SRM results were compared to results using more typical methods, and recommendations were made for using same-gender vs. cross-gender ratings and summary affective preference scores., (Copyright (c) 2009 The Association for Professionals in Services for Adolescents. Published by Elsevier Ltd. All rights reserved.)

Factor H (CFH) autoantibodies are associated with atypical hemolytic uremic syndrome (aHUS). Peritransplantation plasma exchange therapy and intensification of immunosuppression, with adjuvant use of anti-CD20 monoclonal antibodies has recently been advocated for cases of CFH-autoantibody associated aHUS. In this report, we describe successful deceased donor renal transplantation in a case of CFH-autoantibody associated aHUS with combined CFHR1 and 3 deficiency in addition to the CFH sequence variant, (cG2850T, pGln950His). CFH-autoantibodies were detected 2 weeks prior to transplantation. Disease recurrence was not observed using basiliximab, an IL2-receptor antagonist and high-dose corticosteroids with mycophenolate mofetil. Adjuvant therapies such as Rituximab nor intensification of plasma therapy were employed. Consequently, careful consideration needs to be given to the use of additional immunosuppression in certain cases of CFH-autoantibody associated aHUS. Serial measurement of CFH-autoantibodies is required in the immediate pre- and posttransplantation period to further clarify their role as a factor in the recurrence of aHUS posttransplantation. Furthermore, delineation of the functional significance of CFH-autoantibodies is warranted in individual cases.