The History of Cystinosis: Lessons for Clinical Management

Cystinosis is a rare disorder, and, accordingly, progress on the understanding and treatment of this disease has been relatively slow. Although cystinosis was identified over 100 years ago, the history of cystinosis is marked by a few sudden leaps forward in our understanding rather than by a sustained research effort fuelled by the larger research community. Major conceptual break-throughs include (a) its discovery in 1903, (b) recognition of the renal Fanconi syndrome, (c) realization that tissue accumulation of cystine reflects a defective channel in the lysosomal membrane, (d) translation of this discovery to trials of cysteamine, (e) discovery of the CTNS gene, and (f) report of successful stem cell therapy in the cystinotic mouse. This paper focuses on the importance management lessons from these milestones and the potential new therapeutic strategies which may be looming in the near future

Practitioner Review: Therapeutics of unipolar major depressions in adolescents.

BACKGROUND: Over the past two decades new and key randomized controlled trials have reported the efficacy, clinical and cost effectiveness of psychological and pharmacological treatments for adolescents with major depression. METHODS: The literature was searched through pubmed, psychinfo, scopus and web of science for randomized controlled trials of current major depression together with meta-analyses and systematic reviews of trials between 2000 and 2017. Those specific to the adolescent years (11-18 years) were taken as the primary source for this narrative review. Additional selected studies in adults were used to illustrate methodological issues. RESULTS: Manualized psychological therapies and the SSRI fluoxetine are more effective than active placebo in the treatment of major depressions. Mild to moderate illnesses attending community-based services are likely to benefit from psychological treatment alone. Moderately to severely ill patients attending clinic and hospital services are likely to benefit from monotherapies or combining psychological and pharmacological treatment. Antidepressants carry a small but significant side-effect risk including increased suicidality. Side effects from psychotherapies are somewhat lower but specific negative consequences remain less well characterized. There is some evidence that CBT-based approaches prevent onset of major depression episode in well adolescents at high-risk. Other psychological interventions have not been adequately studied. There has been only limited identification of treatment moderators and no clear understanding of therapeutic mechanisms. CONCLUSIONS: There is now a range of clinically effective treatments for depressed adolescents. Future research needs to reveal moderators of and mechanisms for individual differences to treatment response, determine psychotherapies of value for milder depressions, enhance our understanding of safety and side-effects for all treatments, and consider how to reduce and treat treatment-resistant cases.The IMPACT study was funded by an award to IMG from the National Institute for Health Research (NIHR) Health Technology Assessment (HTA) programme (project number 06/05/01). IMG is also supported by a strategic award from the Wellcome Trust to the University of Cambridge and University College London (095844/Z/11/Z)

Tubular Diseases and Stones Seen From Pediatric and Adult Nephrology Perspectives

The tubular system of the kidneys is a complex series of morphologic and functional units orchestrating the content of tubular fluid as it flows along the nephron and collecting ducts. Renal tubules maintain body water, regulate electrolytes and acid-base balance, reabsorb precious organic solutes, and eliminate specific metabolites, toxins, and drugs. In addition, decisive mechanisms to adjust blood pressure are governed by the renal tubules. Genetic as well as acquired disorders of these tubular functions may cause serious diseases that manifest both in childhood and adulthood. This article addresses a selection of tubulopathies and the underlying pathomechanisms, while highlighting the important differences in pediatric and adult nephrology care. These range from rare monogenic conditions such as nephrogenic diabetes insipidus, cystinosis, and Bartter syndrome that present in childhood, to the genetic and acquired tubular pathologies causing hypertension or nephrolithiasis that are more prevalent in adults. Both pediatric and adult nephrologists must be aware of these conditions and the age-dependent manifestations that warrant close interaction between the two subspecialties

Cortical thickness gradients in structural hierarchies.

MRI, enabling in vivo analysis of cortical morphology, offers a powerful tool in the assessment of brain development and pathology. One of the most ubiquitous measures used-the thickness of the cortex-shows abnormalities in a number of diseases and conditions, but the functional and biological correlates of such alterations are unclear. If the functional connotations of structural MRI measures are to be understood, we must strive to clarify the relationship between measures such as cortical thickness and their cytoarchitectural determinants. We therefore sought to determine whether patterns of cortical thickness mirror a key motif of the cortex, specifically its structural hierarchical organisation. We delineated three sensory hierarchies (visual, somatosensory and auditory) in two species-macaque and human-and explored whether cortical thickness was correlated with specific cytoarchitectural characteristics. Importantly, we controlled for cortical folding which impacts upon thickness and may obscure regional differences. Our results suggest that an easily measurable macroscopic brain parameter, namely, cortical thickness, is systematically related to cytoarchitecture and to the structural hierarchical organisation of the cortex. We argue that the measurement of cortical thickness gradients may become an important way to develop our understanding of brain structure-function relationships. The identification of alterations in such gradients may complement the observation of regionally localised cortical thickness changes in our understanding of normal development and neuropsychiatric illnesses.We thank Claus Hilgetag and Sarah Beul for valuable input and Helen Barbas for providing macaque data. Human data were provided by the Human Connectome Project, WU-Minn Consortium (Principal Investi- gators: David Van Essen and Kamil Ugurbil; 1U54MH091657) funded by the 16 NIH Institutes and Centers that support the NIH Blueprint for Neuroscience Research, and by the McDonnell Center for Systems Neuroscience at Washington University. KW is supported by the Wellcome Trust and the University of Cambridge MB/PhD Programme, IG by a Wellcome Trust Strategic Award (RNAG/260) and LR and PF by the Bernard Wolfe Health Neuroscience Fund and Wellcome Trust.This is the final published manuscript. It first appeared at http://www.sciencedirect.com/science/article/pii/S1053811915001378

Predicting dropout in adolescents receiving therapy for depression.

OBJECTIVE: Therapy dropout is a common occurrence, especially in adolescence. This study investigated whether dropout could be predicted from a range of child, family, and treatment factors in a sample of adolescents receiving therapy for depression. METHOD: This study draws on data from 406 participants of the IMPACT study, a randomized controlled trial, investigating three types of therapy in the treatment of adolescent depression. Logistic regression was used to estimate the effects of predictors on the odds of dropout. RESULTS: Few pre-treatment predictors of dropout were found, with the only significant predictors being older age, antisocial behaviour, and lower scores of verbal intelligence. Missed sessions and poorer therapeutic alliance early in treatment also predicted dropout. Most child and family factors investigated were not significantly associated with dropout. CONCLUSIONS: There may be little about depressed adolescents' presentation prior to therapy starting that indicates their risk of dropout. However, within-treatment factors indicated that warning signs of dropout may be identifiable during the initial phase of therapy. Identifying and targeting early treatment indicators of dropout may provide possibilities for improving engagement. Clinical and methodological significance of this article: In the literature, a great deal of attention has been paid to child and family factors that predict therapy dropout, yet in this study, few pre-treatment characteristics were predictive of dropout. However, findings revealed possible warning signs of dropout in the early part of treatment, as poor therapeutic alliance and missed sessions were both found to be predictive of dropout. These findings call for therapists to be aware of such warning signs and clinical guidelines for managing cases at risk of dropout are warranted

Poor family functioning mediates the link between childhood adversity and adolescent non-suicidal self-injury

Background: Non-suicidal self-injury (NSSI) is a common harmful behavior during adolescence. Exposure to childhood family adversity (CFA) is associated with subsequent emergence of NSSI during adolescence. However, the pathways through which this early environmental risk may operate are not clear. Aims: We tested four alternative hypotheses to explain the association between CFA and adolescent-onset NSSI. Methods: A community sample of n = 933 fourteen year olds with no history of NSSI were followed for three years. Results: Poor family functioning at age 14 mediated the association between CFA before age 5 and subsequent onset of NSSI between 14-17 years. Conclusion: The findings support the cumulative suboptimal environmental hazards (proximal family relationships as a mediator) hypothesis. Improving the family environment at age 14 may mitigate the effects of CFA on adolescent onset of NSSI.MC was funded by a doctoral scholarship from the Gates Cambridge Trust. ALvH is funded by a Royal Society Dorothy Hodgkin Fellowship (No DH150176). PBJ by the NIHR CLAHRC East of England. The study was funded by the Wellcome Trust (Grant no. 074296)

A human ALDH1A2 gene variant is associated with increased newborn kidney size and serum retinoic acid

Nephron number varies widely between 0.3 and 1.3 million per kidney in humans. During fetal life, the rate of nephrogenesis is influenced by local retinoic acid (RA) level such that even moderate maternal vitamin A deficiency limits the final nephron number in rodents. Inactivation of genes in the RA pathway causes renal agenesis in mice; however, the impact of retinoids on human kidney development is unknown. To resolve this, we tested for associations between variants of genes involved in RA metabolism (ALDH1A2, CYP26A1, and CYP26B1) and kidney size among normal newborns. Homozygosity for a common (1 in 5) variant, rs7169289(G), within an Sp1 transcription factor motif of the ALDH1A2 gene, showed a significant 22% increase in newborn kidney volume when adjusted for body surface area. Infants bearing this allele had higher umbilical cord blood RA levels compared to those with homozygous wild-type ALDH1A2 rs7169289(A) alleles. Furthermore, the effect of the rs7169289(G) variant was evident in subgroups with or without a previously reported hypomorphic RET 1476(A) proto-oncogene allele that is critical in determining final nephron number. As maternal vitamin A deficiency is widespread in developing countries and may compromise availability of retinol for fetal RA synthesis, our study suggests that the ALDH1A2 rs7169289(G) variant might be protective for such individuals

Measurement Invariance in Longitudinal Bifactor Models: Review and Application Based on the p Factor.

Bifactor models are increasingly being utilized to study latent constructs such as psychopathology and cognition, which change over the lifespan. Although longitudinal measurement invariance (MI) testing helps ensure valid interpretation of change in a construct over time, this is rarely and inconsistently performed in bifactor models. Our review of MI simulation literature revealed that only one study assessed MI in bifactor models under limited conditions. Recommendations for how to assess MI in bifactor models are suggested based on existing simulation studies of related models. Estimator choice and influence of missing data on MI are also discussed. An empirical example based on a model of the general psychopathology factor (p) elucidates our recommendations, with the present model of p being the first to exhibit residual MI across gender and time. Thus, changes in the ordered-categorical indicators can be attributed to changes in the latent factors. However, further work is needed to clarify MI guidelines for bifactor models, including considering the impact of model complexity and number of indicators. Nonetheless, using the guidelines justified herein to establish MI allows findings from bifactor models to be more confidently interpreted, increasing their comparability and utility

Profiles of family-focused adverse experiences through childhood and early adolescence: the ROOTS project a community investigation of adolescent mental health.

BACKGROUND: Adverse family experiences in early life are associated with subsequent psychopathology. This study adds to the growing body of work exploring the nature and associations between adverse experiences over the childhood years. METHODS: Primary carers of 1143 randomly recruited 14-year olds in Cambridgeshire and Suffolk, UK were interviewed using the Cambridge Early Experiences Interview (CAMEEI) to assess family-focused adversities. Adversities were recorded retrospectively in three time periods (early and later childhood and early adolescence). Latent Class Analysis (LCA) grouped individuals into adversity classes for each time period and longitudinally. Adolescents were interviewed to generate lifetime DSM-IV diagnoses using the K-SADS-PL. The associations between adversity class and diagnoses were explored. RESULTS: LCA generated a 4-class model for each time period and longitudinally. In early childhood 69% were allocated to a low adversity class; a moderate adversity class (19%) showed elevated rates of family loss, mild or moderate family discord, financial difficulties, maternal psychiatric illness and higher risk for paternal atypical parenting; a severe class (6%) experienced higher rates on all indicators and almost exclusively accounted for incidents of child abuse; a fourth class, characterised by atypical parenting from both parents, accounted for the remaining 7%. Class membership was fairly stable (~ 55%) over time with escape from any adversity by 14 years being uncommon. Compared to those in the low class, the odds ratio for reported psychopathology in adolescents in the severe class ranged from 8 for disruptive behaviour disorders through to 4.8 for depressions and 2.0 for anxiety disorders. Only in the low adversity class did significantly more females than males report psychopathology. CONCLUSIONS: Family adversities in the early years occur as multiple rather than single experiences. Although some children escape adversity, for many this negative family environment persists over the first 15 years of life. Different profiles of family risk may be associated with specific mental disorders in young people. Sex differences in psychopathologies may be most pronounced in those exposed to low levels of family adversities.This is the published version of the article. It was published in BMC Psychiatry by BioMed Central. The online version can be found here: http://www.biomedcentral.com/1471-244X/11/109

Behavioral measures of impulsivity and compulsivity in adolescents with nonsuicidal self-injury.

BACKGROUND: Nonsuicidal self-injury (NSSI) is prevalent among adolescents and research is needed to clarify the mechanisms which contribute to the behavior. Here, the authors relate behavioral neurocognitive measures of impulsivity and compulsivity to repetitive and sporadic NSSI in a community sample of adolescents. METHODS: Computerized laboratory tasks (Affective Go/No-Go, Cambridge Gambling Task, and Probabilistic Reversal Task) were used to evaluate cognitive performance. Participants were adolescents aged 15 to 17 with (n = 50) and without (n = 190) NSSI history, sampled from the ROOTS project which recruited adolescents from secondary schools in Cambridgeshire, UK. NSSI was categorized as sporadic (1-3 instances per year) or repetitive (4 or more instances per year). Analyses were carried out in a series of linear and negative binomial regressions, controlling for age, gender, intelligence, and recent depressive symptoms. RESULTS: Adolescents with lifetime NSSI, and repetitive NSSI specifically, made significantly more perseverative errors on the Probabilistic Reversal Task and exhibited significantly lower quality of decision making on the Cambridge Gambling Task compared to no-NSSI controls. Those with sporadic NSSI did not significantly differ from no-NSSI controls on task performance. NSSI was not associated with behavioral measures of impulsivity. CONCLUSIONS: Repetitive NSSI is associated with increased behavioral compulsivity and disadvantageous decision making, but not with behavioral impulsivity. Future research should continue to investigate how neurocognitive phenotypes contribute to the onset and maintenance of NSSI, and determine whether compulsivity and addictive features of NSSI are potential targets for treatment