Alternative Strategies for the Treatment of Classical Congenital Adrenal Hyperplasia: Pitfalls and Promises

Despite decades of different treatment algorithms, the management of congenital adrenal hyperplasia (CAH) remains clinically challenging. This is due to the inherent difficulty of suppressing adrenal androgen production using near physiological dosing of glucocorticoids (GC). As a result, alternating cycles of androgen versus GC excess can occur and may lead to short stature, obesity, virilization, and alterations in puberty. Novel therapeutic alternatives, including new and more physiological means of GC delivery, inhibitors at the level of CRH or ACTH secretion and/or action, as well as “rescue strategies”, such as GnRH analogs, anti-androgens, aromatase inhibitors, and estrogen receptor blockers, are available; many of these agents, however, still require active investigation in CAH. Bilateral adrenalectomy is effective but it is also still an experimental approach. Gene therapy and stem cells, to provide functional adrenal cortical tissue, are at preclinical stage but provide exciting avenues for a potential cure for CAH

Cell Cycle-Dependent Localization of Voltage-Dependent Calcium Channels and the Mitotic Apparatus in a Neuroendocrine Cell Line(AtT-20)

Changes in intracellular calcium are necessary for the successful progression of mitosis in many cells. Both elevation and reduction in intracellular calcium can disrupt mitosis by mechanisms that remain ill defined. In this study we explore the role of transmembrane voltage-gated calcium channels (CaV channels) as regulators of mitosis in the mouse corticotroph cell line (AtT-20). We report that the nifedipine-sensitive isoform CaV1.2 is localized to the “poleward side” of kinetechores during metaphase and at the midbody during cytokinesis. A second nifedipine-sensitive isoform, CaV1.3, is present at the mid-spindle zone in telophase, but is also seen at the midbody. Nifedipine reduces the rate of cell proliferation, and, utilizing time-lapse microscopy, we show that this is due to a block at the prometaphase stage of the cell cycle. Using Fluo-4 we detect calcium fluxes at sites corresponding to the mid-spindle zone and the midbody region. Another calcium dye, Fura PE3/AM, causes an inhibition of mitosis prior to anaphase that we attribute to a chelation of intracellular calcium. Our results demonstrate a novel, isoform-specific localization of CaV1 channels during cell division and suggest a possible role for these channels in the calcium-dependent events underlying mitotic progression in pituitary corticotrophs

"I Am a Total...Loser" - The Role of Interpretation Biases in Youth Depression

Negative interpretation biases have been found to characterize adults with depression and to be involved in the development and maintenance of the disorder. However, less is known about their role in youth depression. The present study investigated i) whether negative interpretation biases characterize children and adolescents with depression and ii) to what extent these biases are more pronounced in currently depressed youth compared to youth at risk for depression (as some negative interpretation biases have been found already in high-risk youth before disorder onset). After a negative mood induction interpretation biases were assessed with two experimental tasks: Ambiguous Scenarios Task (AST) and Scrambled Sentences Task (SST) in three groups of 9-14-year-olds: children and adolescents with a diagnosis of major depression (n = 32), children and adolescents with a high risk for depression (children of depressed parents; n = 48), as well as low-risk children and adolescents (n = 42). Depressed youth exhibited substantially more negative interpretation biases than both high-risk and low-risk groups (as assessed with both tasks), while the high-risk group showed more negative interpretation biases than the low-risk group only as assessed via the SST. The results indicate that the negative interpretation biases that are to some extent already present in high-risk populations before disorder onset are strongly amplified in currently depressed youth. The different findings for the two tasks suggest that more implicit interpretation biases (assessed with the SST) might represent cognitive vulnerabilities for depression whereas more explicit interpretation biases (assessed with the AST) may arise as a consequence of depressive symptomatology

Qualitative evaluation of a preventive intervention for the offspring of parents with a history of depression

Background: Meta-analyses of randomised controlled trials suggest that psychological interventions to reduce children’s risk of depression are effective. Nevertheless, these effects are modest and diminish over time. The Medical Research Council recommends a mixed-methods approach to the evaluation of complex interventions. By gaining a more thorough understanding of participants’ perspectives, qualitative evaluations of preventive interventions could improve their efficacy, longevity and transfer into clinical practice. Methods: 18 parents and 22 children who had received a 12-session family- and group-based cognitivebehavioural intervention to prevent youth depression as part of a randomised controlled trial took part in semistructured interviews or a focus group about aspects which had been perceived as helpful, elements they were still using after the intervention had ended, and suggestions they had for improving the intervention. Results: The chance to openly share and discuss their experiences of depression within and between families was considered helpful by both children and parents. Children benefitted the most from learning coping strategies for dealing with stress and many still used them in everyday life. Parents profited mostly from increasing positive family time, but noted that maintaining new routines after the end of the intervention proved difficult. Participants were generally content with the intervention but commented on how tiring and time consuming it was. Conclusions: Managing parents’ expectations of family-based interventions in terms of their own mental health needs (versus those of their children) and leaving more room for open discussions may result in interventions which are more appealing to participating families. Increasing intervals between sessions may be one means of improving the longevity of interventions. Trial registration: The original RCT this evaluation is a part of was registered under NCT02115880

Biased Maintenance of Attention on Sad Faces in Clinically Depressed Youth: An Eye-Tracking Study

The role of negative attention biases (AB), central to cognitive models of adult depression, is yet unclear in youth depression. We investigated negative AB in depressed compared to healthy youth and tested whether AB are more pronounced in depressed than at-risk youth. Negative AB was assessed for sad and angry faces with an eye-tracking paradigm [Passive Viewing Task (PVT)] and a behavioural task [Visual Search Task (VST)], comparing three groups of 9–14-year-olds: youth with major depression (MD; n = 32), youth with depressed parents (high-risk; HR; n = 49) and youth with healthy parents (low-risk; LR; n = 42). The PVT revealed MD participants to maintain attention longer on sad faces compared to HR, but not LR participants. This AB correlated positively with depressive symptoms. The VST revealed no group differences. Our results provide preliminary evidence for a negative AB in maintenance of attention on disorder-specific emotional information in depressed compared to at-risk youth

An Eye-Tracking Study of Attention Biases in Children at High Familial Risk for Depression and Their Parents with Depression

Attention biases (AB) are a core component of cognitive models of depression yet it is unclear what role they play in the transgenerational transmission of depression. 44 children (9-14 years) with a high familial risk of depression (HR) were compared on multiple measures of AB with 36 children with a low familial risk of depression (LR). Their parents: 44 adults with a history of depression (HD) and 36 adults with no history of psychiatric disorder (ND) were also compared. There was no evidence of group differences in AB; neither between the HR and LR children, nor between HD and ND parents. There was no evidence of a correlation between parent and child AB. The internal consistency of the tasks varied greatly. The Dot-Probe Task showed unacceptable reliability whereas the behavioral index of the Visual-Search Task and an eye-tracking index of the Passive-Viewing Task showed better reliability. There was little correlation between the AB tasks and the tasks showed minimal convergence with symptoms of depression or anxiety. The null-findings of the current study contradict our expectations and much of the previous literature. They may be due to the poor psychometric properties associated with some of the AB indices, the unreliability of AB in general, or the relatively modest sample size. The poor reliability of the tasks in our sample suggest caution should be taken when interpreting the positive findings of previous studies which have used similar methods and populations

SEU Robustness, Total Dose Radiation Hardness and Analogue Performance of the Beetle Chip

The Beetle is a 128 channel readout chip for silicon strip detectors in LHCb. In addition to the pipelined readout path known from the RD20 architecture which can be used either in analogue or binary mode, the Beetle features an additional prompt binary readout path, used for the LHCb pile-up veto counters and a triple-redundant layout of the control logic. It is manufactured in commercial 0.25 µm CMOS technology using radiation hard design techniques. In addition to a total dose irradiation with X-rays, an SEU irradiation test with 65 MeV protons was performed with Beetle1.3. The results of this test are presented together with new results from the Beetle versions 1.3, 1.4 and 1.5, which were submitted in the Beetle ER engineering run in May 2004

The LHCb Silicon Inner Tracker

The inner part of the LHCb main tracking system will be realized in a silicon microstrip technology. The experimental requirements suggest approximately 20 cm-long ladders and a readout pitch of around 200 m. The LHCb Inner Tracker system will consist of three tracking stations having a total of 12 detection layers summing to an overall silicon surface area of approximately 4.2 m2. A report about the status of the current R&D of the silicon ladders and tracking stations of the LHCb Inner Tracker is given

Interventions to support people exposed to adverse childhood experiences : systematic review of systematic reviews

BACKGROUND: Adverse Childhood Experiences (ACEs) such as abuse, neglect or household adversity may have a range of serious negative impacts. There is a need to understand what interventions are effective to improve outcomes for people who have experienced ACEs. METHODS: Systematic review of systematic reviews. We searched 18 database sources from 2007 to 2018 for systematic reviews of effectiveness data on people who experienced ACEs aged 3-18, on any intervention and any outcome except incidence of ACEs. We included reviews with a summary quality score (AMSTAR) of 5.5 or above. RESULTS: Twenty-five reviews were included. Most reviews focus on psychological interventions and mental health outcomes. The strongest evidence is for cognitive-behavioural therapy for people exposed to abuse. For other interventions - including psychological therapies, parent training, and broader support interventions - the findings overall are inconclusive, although there are some positive results. CONCLUSIONS: There are significant gaps in the evidence on interventions for ACEs. Most approaches focus on mitigating individual psychological harms, and do not address the social pathways which may mediate the negative impacts of ACEs. Many negative impacts of ACEs (e.g. on health behaviours, social relationships and life circumstances) have also not been widely addressed by intervention studies