Gene–Environment Interactions and Intermediate Phenotypes: Early Trauma and Depression

This review focuses on current research developments in the study of gene by early life stress (ELS) interactions and depression. ELS refers to aversive experiences during childhood and adolescence such as sexual, physical or emotional abuse, emotional or physical neglect as well as parental loss. Previous research has focused on investigating and characterizing the specific role of ELS within the pathogenesis of depression and linking these findings to neurobiological changes of the brain, especially the stress response system. The latest findings highlight the role of genetic factors that increase vulnerability or, likewise, promote resilience to depression after childhood trauma. Considering intermediate phenotypes has further increased our understanding of the complex relationship between early trauma and depression. Recent findings with regard to epigenetic changes resulting from adverse environmental events during childhood promote current endeavors to identify specific target areas for prevention and treatment schemes regarding the long-term impact of ELS. Taken together, the latest research findings have underscored the essential role of genotypes and epigenetic processes within the development of depression after childhood trauma, thereby building the basis for future research and clinical interventions

DNA copy number changes define spatial patterns of heterogeneity in colorectal cancer

Genetic heterogeneity between and within tumours is a major factor determining cancer progression and therapy response. Here we examined DNA sequence and DNA copy-number heterogeneity in colorectal cancer (CRC) by targeted high-depth sequencing of 100 most frequently altered genes. In 97 samples, with primary tumours and matched metastases from 27 patients, we observe inter-tumour concordance for coding mutations; in contrast, gene copy numbers are highly discordant between primary tumours and metastases as validated by fluorescent in situ hybridization. To further investigate intra-tumour heterogeneity, we dissected a single tumour into 68 spatially defined samples and sequenced them separately. We identify evenly distributed coding mutations in APC and TP53 in all tumour areas, yet highly variable gene copy numbers in numerous genes. 3D morpho-molecular reconstruction reveals two clusters with divergent copy number aberrations along the proximal–distal axis indicating that DNA copy number variations are a major source of tumour heterogeneity in CRC

Sleep Disruption and Daytime Sleepiness Correlating with Disease Severity and Insulin Resistance in Non-Alcoholic Fatty Liver Disease: A Comparison with Healthy Controls

BACKGROUND & AIMS: Sleep disturbance is associated with the development of obesity, diabetes and hepatic steatosis in murine models. Hepatic triglyceride accumulation oscillates in a circadian rhythm regulated by clock genes, light-dark cycle and feeding time in mice. The role of the sleep-wake cycle in the pathogenesis of human non-alcoholic fatty liver disease (NAFLD) is indeterminate. We sought to detail sleep characteristics, daytime sleepiness and meal times in relation to disease severity in patients with NAFLD. METHODS: Basic Sleep duration and latency, daytime sleepiness (Epworth sleepiness scale), Pittsburgh sleep quality index, positive and negative affect scale, Munich Chronotype Questionnaire and an eating habit questionnaire were assessed in 46 patients with biopsy-proven NAFLD and 22 healthy controls, and correlated with biochemical and histological parameters. RESULTS: In NAFLD compared to healthy controls, time to fall asleep was vastly prolonged (26.9 vs. 9.8 min., p = 0.0176) and sleep duration was shortened (6.3 vs. 7.2 hours, p = 0.0149). Sleep quality was poor (Pittsburgh sleep quality index 8.2 vs. 4.7, p = 0.0074) and correlated with changes in affect. Meal frequency was shifted towards night-times (p = 0.001). In NAFLD but not controls, daytime sleepiness significantly correlated with liver enzymes (ALAT [r = 0.44, p = 0.0029], ASAT [r = 0.46, p = 0.0017]) and insulin resistance (HOMA-IR [r = 0.5, p = 0.0009]) independent of cirrhosis. In patients with fibrosis, daytime sleepiness correlated with the degree of fibrosis (r = 0.364, p = 0.019). CONCLUSIONS: In NAFLD sleep duration was shortened, sleep onset was delayed and sleep quality poor. Food-intake was shifted towards the night. Daytime sleepiness was positively linked to biochemical and histologic surrogates of disease severity. The data may indicate a role for sleep-wake cycle regulation and timing of food-intake in the pathogenesis of human NAFLD as suggested from murine models

Dose-dependent changes in real-life affective well-being in healthy community-based individuals with mild to moderate childhood trauma exposure

Background Childhood trauma exposures (CTEs) are frequent, well-established risk factor for the development of psychopathology. However, knowledge of the effects of CTEs in healthy individuals in a real life context, which is crucial for early detection and prevention of mental disorders, is incomplete. Here, we use ecological momentary assessment (EMA) to investigate CTE load-dependent changes in daily-life affective well-being and psychosocial risk profile in n = 351 healthy, clinically asymptomatic, adults from the community with mild to moderate CTE. Findings EMA revealed significant CTE dose-dependent decreases in real-life affective valence (p = 0.007), energetic arousal (p = 0.032) and calmness (p = 0.044). Psychosocial questionnaires revealed a broad CTE-related psychosocial risk profile with dose-dependent increases in mental health risk-associated features (e.g., trait anxiety, maladaptive coping, loneliness, daily hassles; p values < 0.003) and a corresponding decrease in factors protective for mental health (e.g., life satisfaction, adaptive coping, optimism, social support; p values < 0.021). These results were not influenced by age, sex, socioeconomic status or education. Conclusions Healthy community-based adults with mild to moderate CTE exhibit dose-dependent changes in well-being manifesting in decreases in affective valence, calmness and energy in real life settings, as well as a range of established psychosocial risk features associated with mental health risk. This indicates an approach to early detection, early intervention, and prevention of CTE-associated psychiatric disorders in this at-risk population, using ecological momentary interventions (EMI) in real life, which enhance established protective factors for mental health, such as green space exposure, or social support

Alterations of nocturnal activity in rats following subchronic oral administration of the neurotoxin 1-trichloromethyl-1,2,3,4-tetrahydro-β-carboline

1-Trichloromethyl-1,2,3,4-tetrahydro-β-carboline (TaClo) is neurotoxic when administered to the brain and alters motor behaviour following intraperitoneal administration. We have assessed the long-term effects of oral TaClo administration on nocturnal motor behaviour in rats. Two groups of rats received TaClo orally at a dose of either 0.2 or 0.4 mg/kg twice daily for 7 weeks. The control group was given saline. No change in locomotor activity was observed 4–9 days after the end of the 7-week administration of TaClo. In addition, the spontaneous motor activity was altered dose-dependently 9 months after oral TaClo administration, with an increase in the low-dose TaClo group and a decrease in the high-dose group. Oral administration of TaClo in rats may be useful in investigating the hypothesis that in Parkinson’s disease, an unknown pathogenic factor crossing the intestinal mucosa barrier can induce neurodegenerative processes eventually affecting the entire brain

Relationship between Borderline Personality Disorder, Emotional Availability, and Cortisol Output in Mother-Child Dyads

Background: Mothers with borderline personality disorder (BPD) often show altered emotional availability toward their own child and heightened stress vulnerability. The aims of the present study were (1) to examine total cortisol output in saliva during mother-child interaction in mothers with BPD and their children and (2) to test whether maternal nonhostility as a subscale of emotional availability mediates the relationship between maternal BPD and child total cortisol output. Methods: We investigated 16 mothers with BPD and 30 healthy control mothers (HC) and 29 children of mothers with BPD and 33 children of HC mothers. Children were between 5 and 12 years old. Salivary cortisol was collected prior to and twice after an episode of a 21-min standardized play situation between mother and child. Nonhostility was rated using the emotional availability scales. Analyses of covariance were computed to test for group differences in total cortisol output (measured with area under the curve with respect to ground). Pearson's correlation was calculated to test the association between maternal and child total cortisol output. To test the second question, a mediation analysis according to Preacher and Hayes was conducted. Results: Mothers with BPD and their children had lower total cortisol output. Maternal and child total cortisol output was significantly correlated. Contrary to our hypothesis, maternal nonhostility did not mediate the relationship between BPD and child total cortisol output. Conclusion: Results imply that the hormonal stress activity of mothers with BPD and their children is altered, which may reflect modified stress regulation and stress vulnerability in mother and child and may impact on mother-child interaction. The finding of a positive association between mother's and child total cortisol output could indicate an intergenerational transmission of these alterations

Immediate impact of child maltreatment on mental, developmental, and physical health trajectories

Objective: The immediate impact of child maltreatment on health and developmental trajectories over time is unknown. Longitudinal studies starting in the direct aftermath of exposure with repeated follow-up are needed. Method: We assessed health and developmental outcomes in 6-month intervals over 2 years in 173 children, aged 3-5 years at study entry, including 86 children with exposure to emotional and physical abuse or neglect within 6 months and 87 nonmaltreated children. Assessments included clinician-administered, self- and parent-report measures of psychiatric and behavioral symptoms, development, and physical health. Linear mixed models and latent growth curve analyses were used to contrast trajectories between groups and to investigate the impact of maltreatment features on trajectories. Results: Maltreated children exhibited greater numbers of psychiatric diagnoses (b = 1.998, p < .001), externalizing (b = 13.29, p < .001) and internalizing (b = 11.70, p < .001) symptoms, impairments in cognitive (b = -11.586, p < .001), verbal (b = -10.687, p < .001), and motor development (b = -7.904, p = .006), and greater numbers of medical symptoms (b = 1.021, p < .001) compared to nonmaltreated children across all time-points. Lifetime maltreatment severity and/or age at earliest maltreatment exposure predicted adverse outcomes over time. Conclusion: The profound, immediate, and stable impact of maltreatment on health and developmental trajectories supports a biological embedding model and provides foundation to scrutinize the precise underlying mechanisms. Such knowledge will enable the development of early risk markers and mechanism-driven interventions that mitigate adverse trajectories in maltreated children

S-Adenosyl-Methionine and Betaine Improve Early Virological Response in Chronic Hepatitis C Patients with Previous Nonresponse

Treatment of chronic hepatitis C (CHC) with pegylated interferon (pegIFN ) and ribavirin results in a sustained response in approximately half of patients. Viral interference with IFN signal transduction through the Jak-STAT pathway might be an important factor underlying treatment failure. S-adenosyl-L-methionine (SAMe) and betaine potentiate IFN signaling in cultured cells that express hepatitis C virus (HCV) proteins, and enhance the inhibitory effect of IFN on HCV replicons. We have performed a clinical study with the aim to evaluate efficacy and safety of the addition of SAMe and betaine to treatment of CHC with pegIFN /ribavirin

Ribociclib-induced liver injury: a case report

BackgroundIdiosyncratic drug-induced liver injury (DILI) is a rare, unpredictable hepatic adverse event and the most common cause of acute liver failure in Europe and the US. Ribociclib is a potent Cyclin-dependent kinase 4 and 6 (CDK4/6)-inhibitor administered for advanced hormone-receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative breast cancer. Previous reports have shown hepatotoxicity without liver necrosis related to ribociclib.Case presentationA 41-year-old female patient with primary metastatic HR-positive, HER2-negative breast cancer developed liver enzyme elevation under treatment with ribociclib. Ribociclib was withdrawn 8 weeks after initiation due to liver enzyme elevation. A liver biopsy, performed due to further enzyme increase (peak ALT 2836 U/l), onset of jaundice (peak bilirubin 353 µmol/l) and coagulopathy (INR 1.8) two weeks later, revealed acute hepatitis with 30% parenchymal necrosis. Roussel Uclaf Causality Assessment Method (RUCAM) score was 7 points (probable). Under treatment with prednisone (60mg), initiated 2 weeks after drug withdrawal, and subsequently N-acetylcysteine (Prescott regimen) liver enzymes normalized within 8 weeks along with prednisone tapering.ConclusionThis case illustrates the development of a severe idiosyncratic hepatocellular pattern DILI grade 3 (International DILI Expert Working Group) induced by ribociclib. Routine liver enzyme testing during therapy, immediate hepatologic work-up and treatment interruption in case of liver enzyme elevation are highly recommended. Corticosteroid treatment should be considered in cases of severe necroinflammation

Psychometric properties of the CDC Symptom Inventory for assessment of Chronic Fatigue Syndrome

OBJECTIVES: Validated or standardized self-report questionnaires used in research studies and clinical evaluation of chronic fatigue syndrome (CFS) generally focus on the assessment of fatigue. There are relatively few published questionnaires that evaluate case defining and other accompanying symptoms in CFS. This paper introduces the self-report CDC CFS Symptom Inventory and analyzes its psychometric properties. METHODS: One hundred sixty-four subjects (with CFS, other fatiguing illnesses and non fatigued controls) identified from the general population of Wichita, Kansas were enrolled. Evaluation included a physical examination, a standardized psychiatric interview, three previously validated self-report questionnaires measuring fatigue and illness impact (Medical Outcomes Survey Short-Form-36 [MOS SF-36], Multidimensional Fatigue Inventory [MFI], Chalder Fatigue Scale), and the CDC CFS Symptom Inventory. Based on theoretical assumptions and statistical analyses, we developed several different Symptom Inventory scores and evaluated them on their ability to differentiate between participants with CFS and non-fatigued controls. RESULTS: The Symptom Inventory had good internal consistency and excellent convergent validity. A Total score (all symptoms), Case Definition score (CFS case defining symptoms) and Short Form score (6 symptoms with minimal correlation) differentiated CFS cases from controls. Furthermore, both the Case Definition and Short Form scores distinguished people with CFS from fatigued subjects who did not meet criteria for CFS. CONCLUSION: The Symptom Inventory appears to be a reliable and valid instrument to assess symptoms that accompany CFS. It is a positive addition to existing instruments measuring fatigue because it allows other dimensions of the illness to be assessed. Further research is needed to confirm and replicate the current findings in a normative population