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Although cell transplantation can rescue motor defects in Parkinson's disease (PD) models, whether and how grafts functionally repair damaged neural circuitry in the adult brain is not known. We transplanted hESC-derived midbrain dopamine (mDA) or cortical glutamate neurons into the substantia nigra or striatum of a mouse PD model and found extensive graft integration with host circuitry. Axonal pathfinding toward the dorsal striatum was determined by the identity of the grafted neurons, and anatomical presynaptic inputs were largely dependent on graft location, whereas inhibitory versus excitatory input was dictated by the identity of grafted neurons. hESC-derived mDA neurons display A9 characteristics and restore functionality of the reconstructed nigrostriatal circuit to mediate improvements in motor function. These results indicate similarity in cell-type-specific pre- and post-synaptic integration between transplant-reconstructed circuit and endogenous neural networks, highlighting the capacity of hPSC-derived neuron subtypes for specific circuit repair and functional restoration in the adult brain.

Cutaneous Langerhan’s cell histiocytosis (LCH) is considered a great clinical mimicker and affects the scalp and intertriginous regions although it may be generalized. Cutaneous LCH is commonly misdiagnosed and thus patients can receive inadequate or inappropriate treatment for considerable periods of time. We present a case report of a patient who had LCH that was masquareding as intertrigo for years. With the proper diagnosis the patient had a remarkable response to methotrexate. This case highlights the importance of keeping Langerhan’s cell histiocytosis (LCH) on the differential and once the diagnosis is made, evaluating for extracutaneous LCH.

Background Major Depressive Disorder (MDD) is a leading cause of disease burden worldwide. With the rapid growth of neuroimaging research on relatively small samples, meta-analytic techniques are becoming increasingly important. Here, we aim to clarify the support in fMRI literature for three leading neurobiological models of MDD: limbic-cortical, cortico-striatal and the default mode network. Methods Searches of PubMed and Web of Knowledge, and manual searches, were undertaken in early 2011. Data from 34 case-control comparisons (n=1165) and 6 treatment studies (n=105) were analysed separately with two meta-analytic methods for imaging data: Activation Likelihood Estimation and Gaussian-Process Regression. Results There was broad support for limbic-cortical and cortico-striatal models in the case-control data. Evidence for the role of the default mode network was weaker. Treatment-sensitive regions were primarily in lateral frontal areas. Limitations In any meta-analysis, the increase in the statistical power of the inference comes with the risk of aggregating heterogeneous study pools. While we believe that this wide range of paradigms allows identification of key regions of dysfunction in MDD (regardless of task), we attempted to minimise such risks by employing GPR, which models such heterogeneity. Conclusions The focus of treatment effects in frontal areas indicates that dysregulation here may represent a biomarker of treatment response. Since the dysregulation in many subcortical regions in the case-control comparisons appeared insensitive to treatment, we propose that these act as trait vulnerability markers, or perhaps treatment insensitivity. Our findings allow these models of MDD to be applied to fMRI literature with some confidence. © 2013 The Authors.

Low-income children and adolescents continue to bear a heavy burden of untreated pain and complications from dental disease. To explore why proposals to remediate this problem have not gained traction, the authors interviewed experts involved in efforts to improve the oral health status of low-income and minority children during the past decade. Key informants believe that success requires addressing both consumer demand and provider supply factors. They especially cite the lack of public outcry for more accessible oral health care and the undervaluing of oral health, relative to medical care. Informants were cautiously optimistic that strategies such as health literacy and outreach campaigns, which have helped increase children's physical activity and improve their diets, offer unexplored opportunities for progress.

Background & Aims Co-amoxiclav is one of the most common causes of drug-induced liver injury (DILI). Although there are previous reports of genetic associations between HLA class II and co-amoxiclav-related DILI, studies to date have been based on very small numbers from single centres only. In order to address this problem we have investigated the role of HLA class II DRB1 and DQB1 in 61 cases of co-amoxiclav DILI as part of a UK-wide multicentre study. Methods HLA alleles and genotypes were compared with those of 40 individuals exposed to co-amoxiclav without toxicity (treated controls) and 191 population controls. Results There were two significant findings from the study. First, HLA- DRB1*15 was increased in patients (53%) versus both treated (33%: OR=2.29: 95% CI: 1.00–5.26) and population controls (30%: OR=2.59:95% CI: 1.44–4.68: p =0.002). Second, DRB1*07 was found to be reduced in patients (9.8%) compared to both treated (35%: OR=0.18: 95% CI: 0.06 – 0.52: p=0.0011, pc=0.0154) and population controls (29%: OR=0.266: 95% CI: 0.11 – 0.65: p=0.0019, pc=0.0266). Conclusions These results confirm the previously reported significant genetic risk for HLA- DRB1*15 and also provide evidence of a protective effect of the HLA- DRB1*07 family of alleles. HLA alleles and haplotypes may be particularly important in susceptibility and resistance to co-amoxiclav-DILI, but it remains to be seen whether this effect is due to the identified alleles or others in close linkage disequilibrium elsewhere on the MHC.

Drug-induced liver injury (DILI) is an important cause of serious liver disease. The antimicrobial agent flucloxacillin is a common cause of DILI, but the genetic basis for susceptibility remains unclear. We conducted a genome-wide association (GWA) study using 866,399 markers in 51 cases of flucloxacillin DILI and 282 controls matched for sex and ancestry. The GWA showed an association peak in the major histocompatibility complex (MHC) region with the strongest association (P = 8.7 x 10(-33)) seen for rs2395029[G], a marker in complete linkage disequilibrium (LD) with HLA-B*5701. Further MHC genotyping, which included 64 flucloxacillin-tolerant controls, confirmed the association with HLA-B*5701 (OR = 80.6, P = 9.0 x 10(-19)). The association was replicated in a second cohort of 23 cases. In HLA-B*5701 carrier cases, rs10937275 in ST6GAL1 on chromosome 3 also showed genome-wide significance (OR = 4.1, P = 1.4 x 10(-8)). These findings provide new insights into the mechanism of flucloxacillin DILI and have the potential to substantially improve diagnosis of this serious disease.

How and why do clinical depressive disorders emerge in adolescence? In this Personal View, we present a neurodevelopmental theory to address causes for adolescent onsets of clinical depressive disorders. We argue that theories should account for three perplexing aspects of depressive disorders in adolescence: the episodic nature of depression; differences between sexes in rates of depression across development; and age-differentiated onsets. We consider how theories such as psychosocial acceleration, heterochronic brain development, dual-process models, glucocorticoid vulnerability hypothesis linked to early life stress, and epigenetic and genetic susceptibility might explain some aspects of adolescent depressive disorders. We argue that some synthesis between existing theories might be needed to establish a sufficient neurodevelopmental theoretical framework to explain onsets of depressive disorders in adolescence.

School-based health services have made limited contributions to the well-being of school-age children. However, they have the potential for promoting health and improving service delivery for 50 million children and adolescents enrolled in the nation's schools. Recent changes in health care, particularly the spread of managed care and development of integrated health service networks, have reawakened mainstream interest in school health and created the possibility for strengthening its efficiency and effectiveness. Two promising strategies for enabling school health programs to fulfill their potential are being implemented by the Massachusetts state government and by an Austin, Texas, hospital system. These strategies suggest measures to create either closely linked school and community health systems or fully integrated school/community child health systems that may have widespread benefit for children and their families. Barriers to fully implementing these strategies and replicating them in other communities will include the challenge of securing adequate funding, disagreements regarding the appropriate content of a school health program, and opposition to new staffing and employment arrangements from professional and union organizations. Whether this moment of opportunity yields gains for child health and school health will, for the most part, depend on forces outside school health. Success will be particularly dependent on the degree to which the managed care plans or large health care organizations see value in building more comprehensive child health systems or identify financial benefits from linking more closely with school-based services.