Adrenocortical carcinoma -- improving patient care by establishing new structures.

BACKGROUND: Adrenocortical carcinoma (ACC) is a rare and highly malignant tumour with a poor prognosis. Patients present with signs of steroid hormone excess (e.g., Cushing's syndrome) or symptoms due to an abdominal mass. DIAGNOSIS: In case of an adrenal mass, hormonal workup before surgery is required for differential diagnosis, perioperative management, and for follow-up. The imaging of choice is CT or MRI with MRI being of additional use when invasion of big vessels is suspected. Apart from that, the use of 18-FDG-PET is becoming increasingly established. TREATMENT: Surgical resection is the therapeutic option of choice in stages 1 - 3. In stage 4, the adrenolytic compound mitotane is part of the first-line treatment, but often needs to be combined with cytotoxic chemotherapy. Most patients will eventually have a recurrence, so adjuvant treatment (mitotane/tumour bed radiation) has to be considered in high risk patients, even if randomized controlled trials on adjuvant treatment are still lacking. STRUCTURAL PROGRESS: Several national and European structures have recently been established in order to increase our knowledge of ACC, improve therapeutic options and diagnostic procedures, and promote research. GANIMED, as a Germany-wide network of experts on adrenal diseases, has been founded allowing for improved gathering of data and joint studies. ENSAT (European Network for the Study of Adrenal Tumours) has been brought to life, aiming at European standards for therapy, diagnosis and tumour banking. Since 2003, patients can be enrolled in the German ACC Registry. France and Italy have also developed a central registry to collect nationwide data from patients with ACC. For the first time, patients with metastatic/unresectable ACC can participate in a prospective controlled randomized trial comparing two different cytotoxic chemotherapy regimes (FIRM-ACT).     

Experiences of use of the cerebral palsy hemiplegic hand in young persons treated with upper extremity surgery.

The aim of this qualitative study was to explore the experiences of young persons using their hemiplegic hand in daily life activities following upper extremity surgery (UES). Ten persons, aged 12-24 years, were interviewed individually five to seven years after surgery. The analysis was guided by a comparative method. The findings show that the participants during this period had experienced changes which they related both to the treatment and to development. Data resolved into three main themes. Functional improvements are interwoven into daily life, the hand is easier to use and is used more, and changes in the appearance and in the internal feeling of the arm are of importance. This study reflects the patients' experiences of living with the outcome of UES and yields an important complement to objective, quantitative outcome studies.     

Assessing hematopoietic chimerism after allogeneic stem cell transplantation by multiplexed SNP genotyping using microarrays and quantitative analysis of SNP alleles.

Single-nucleotide polymorphisms (SNPs) have the potential to be particularly useful as markers for monitoring of chimerism after stem cell transplantation (SCT) because they can be analyzed by accurate and robust methods. We used a two-phased minisequencing strategy for monitoring chimerism after SCT. First, informative SNPs with alleles differing between donor and recipient were identified using a multiplex microarray-based minisequencing system screening 51 SNPs to ensure that multiple informative SNPs were detected in each donor-recipient pair. Secondly, the development of chimerism was followed up after SCT by sensitive, quantitative analysis of individual informative SNPs by applying the minisequencing method in a microtiter plate format. Using this panel of SNPs, we identified multiple informative SNPs in nine unrelated and in 16 related donor-recipient pairs. Samples from nine of the donor-recipient pairs taken at time points ranging from 1 month to 8 years after transplantation were available for analysis. In these samples, we monitored the allelic ratios of two or three informative SNPs in individual minisequencing reactions. The results agreed well with the data obtained by microsatellite analysis. Thus, we conclude that the two-phased minisequencing strategy is a useful approach in the following up of patients after SCT.     

Are restrained children under 15 years of age in cars as effectively protected as adults?

AIM: To compare the injury distribution between children and adults, injured as restrained car passengers. METHODS: Population based study of data from a French road trauma registry in 1996-2002. Children under 15 years old were compared with adult casualties according to the distribution of serious injuries in three distinct body regions (head, chest, and abdomen) when they were restrained car passengers. A multivariate logistic regression was performed to quantify the risk of AIS2+ injury (Abbreviated Injury Scale of 2 or more). RESULTS: Among the 7568 casualties who were injured as restrained car passengers in car accidents, 1033 were less than 15 years old. Overall, 35.4% of children and 25.2% of adults were unrestrained. For children and adults, the risk of fatality was significantly reduced when they were restrained, but the percentages of children with Injury Severity Score (ISS) > or =16, were not significantly different between restrained and not restrained casualties. Compared to adults, restrained children aged 5-9 were 2.7 times (OR 2.74; 95% CI 1.17 to 6.43) as likely to sustain an AIS2+ abdominal injury, and tended to be more at risk of AIS2+ head injuries, but were less at risk of AIS2+ chest injuries. CONCLUSIONS: Children aged 5-9 years injured in road accidents as restrained car passengers were more likely to sustain an AIS2+ abdominal injury than adults. This emphasises the need to reinforce educational campaigns aimed not only at getting children into restraint systems, but also insisting on their correct use.     

Action‐Monitoring Alterations as Indicators of Predictive Deficits in Schizophrenia

A flexible and dynamically adjustable behavior is crucial to adapt to a continuously changing environment. In order to optimally adapt, we need to learn from the consequences of our behavior. We usually learn through different kinds of prediction errors, which occur when we experience unexpected situations due to false predictions. With this literature review, we intended to contribute to current etiological models that ascribe various positive symptoms (particularly delusions and hallucinations) in patients with schizophrenia to false prediction errors and deficient predictive learning. We discuss alterations in the electrophysiological measure of the error‐related negativity/error negativity (ERN/Ne) as a global deficit and a trait in schizophrenia, as they have been observed in different samples of patients with schizophrenia, in individuals at high‐risk and individuals with subclinical schizotypal traits. As the ERN/Ne can itself be considered the result of predictive processes (evaluation of current action outcomes as worse than expected), we propose that the reported alterations indicate that patients suffering from schizophrenic illnesses fail to adequately classify the outcomes of their actions as better or worse than expected due to a deficit in self‐monitoring. Furthermore, we discuss results in further action‐monitoring components, such as the correct response negativity (CRN)—a smaller negativity elicited by correct responses; and error positivity (Pe)—a later positivity assumed to reflect conscious error processing. The reported results show normal Pe amplitudes and normal post‐error adjustments (adaptations after committed error to improve performance), indicating an intact later and conscious processing. From the results of diminished differences between ERN/Ne and CRN amplitudes, we conclude a general predictive deficit in early aspects of self‐monitoring associated with positive symptoms in patients with schizophrenia.     

Revise the revised? New dimensions of the neuroanatomical hypothesis of panic disorder

In 2000, Gorman et al. published a widely acknowledged revised version of their 1989 neuroanatomical hypothesis of panic disorder (PD). Herein, a ‘fear network’ was suggested to mediate fear- and anxiety-related responses: panic attacks result from a dysfunctional coordination of ‘upstream’ (cortical) and ‘downstream’ (brainstem) sensory information leading to heightened amygdala activity with subsequent behavioral, autonomic and neuroendocrine activation. Given the emergence of novel imaging methods such as fMRI and the publication of numerous neuroimaging studies regarding PD since 2000, a comprehensive literature search was performed regarding structural (CT, MRI), metabolic (PET, SPECT, MRS) and functional (fMRI, NIRS, EEG) studies on PD, which will be reviewed and critically discussed in relation to the neuroanatomical hypothesis of PD. Recent findings support structural and functional alterations in limbic and cortical structures in PD. Novel insights regarding structural volume increase or reduction, hyper- or hypoactivity, laterality and task-specificity of neural activation patterns emerged. The assumption of a generally hyperactive amygdala in PD seems to apply more to state than trait characteristics of PD, and involvement of further areas in the fear circuit, such as anterior cingulate and insula, is suggested. Furthermore, genetic risk variants have been proposed to partly drive fear network activity. Thus, the present state of knowledge generally supports limbic and cortical prefrontal involvement as originally proposed in the neuroanatomical hypothesis. Some modifications might be suggested regarding a potential extension of the fear circuit, genetic factors shaping neural network activity and neuroanatomically informed clinical subtypes of PD potentially guiding future treatment decisions.     

MORC1 exhibits cross-species differential methylation in association with early life stress as well as genome-wide association with MDD

Early life stress (ELS) is associated with increased vulnerability for diseases in later life, including psychiatric disorders. Animal models and human studies suggest that this effect is mediated by epigenetic mechanisms. In humans, epigenetic studies to investigate the influence of ELS on psychiatric phenotypes are limited by the inaccessibility of living brain tissue. Due to the tissue-specific nature of epigenetic signatures, it is impossible to determine whether ELS induced epigenetic changes in accessible peripheral cells, for example, blood lymphocytes, reflect epigenetic changes in the brain. To overcome these limitations, we applied a cross-species approach involving: (i) the analysis of CD34+ cells from human cord blood; (ii) the examination of blood-derived CD3+ T cells of newborn and adolescent nonhuman primates (Macaca mulatta); and (iii) the investigation of the prefrontal cortex of adult rats. Several regions in MORC1 (MORC family CW-type zinc finger 1; previously known as: microrchidia (mouse) homolog) were differentially methylated in response to ELS in CD34+ cells and CD3+ T cells derived from the blood of human and monkey neonates, as well as in CD3+ T cells derived from the blood of adolescent monkeys and in the prefrontal cortex of adult rats. MORC1 is thus the first identified epigenetic marker of ELS to be present in blood cell progenitors at birth and in the brain in adulthood. Interestingly, a gene-set-based analysis of data from a genome-wide association study of major depressive disorder (MDD) revealed an association of MORC1 with MDD.