LMO2 activation by deacetylation is indispensable for hematopoiesis and T-ALL leukemogenesis.

Hematopoietic transcription factor LIM domain only 2 (LMO2), a member of the TAL1 transcriptional complex, plays an essential role during early hematopoiesis and is frequently activated in T-cell acute lymphoblastic leukemia (T-ALL) patients. Here, we demonstrate that LMO2 is activated by deacetylation on lysine 74 and 78 via the nicotinamide phosphoribosyltransferase (NAMPT)/sirtuin 2 (SIRT2) pathway. LMO2 deacetylation enables LMO2 to interact with LIM domain binding 1 and activate the TAL1 complex. NAMPT/SIRT2-mediated activation of LMO2 by deacetylation appears to be important for hematopoietic differentiation of induced pluripotent stem cells and blood formation in zebrafish embryos. In T-ALL, deacetylated LMO2 induces expression of TAL1 complex target genes HHEX and NKX3.1 as well as LMO2 autoregulation. Consistent with this, inhibition of NAMPT or SIRT2 suppressed the in vitro growth and in vivo engraftment of T-ALL cells via diminished LMO2 deacetylation. This new molecular mechanism may provide new therapeutic possibilities in T-ALL and may contribute to the development of new methods for in vitro generation of blood cells.

Incidence and Outcomes of Bacterial Bloodstream Infections during Acute Graft-versus-Host Disease Involving the Gastrointestinal Tract after Hematopoietic Cell Transplantation.

Despite the association of acute graft-versus-host disease (aGVHD) and bacterial bloodstream infections (BSIs) in hematopoietic cell transplant (HCT) recipients, relatively little is known about BSIs, specifically during gastrointestinal (GI) tract aGVHD (aGHVD-GI). The purpose of this study was to evaluate the incidence, risk factors, and mortality of BSIs complicating aGVHD-GI. This was a retrospective review of adult HCT recipients with grades I to IV aGVHD-GI between January 2009 and October 2017 at Oregon Health and Sciences University. BSIs occurring within 30 days of onset of aGVHD-GI were included. BSIs were categorized as "clinical" or "surveillance" based on chart review. A subgroup analysis of patients with grade IV aGVHD-GI examined potential BSI risk factors and cumulative survival at 30 and 45 days after onset of aGVHD-GI. Included were 229 patients. There were 45 unique BSIs in 39 patients (17%): 31 clinical (68.9%) and 14 surveillance (32.1%). The median time from aGVHD-GI onset to BSI was 18.5 days. BSIs were significantly more common during grade IV aGVHD-GI compared with grades I, II, or III. Fifty-two organisms were isolated during BSIs: 23 (44.2%) gram-positive and 29 (55.8%) gram-negative. Sixteen BSIs (36%) occurred during antibiotic exposure, and those were more likely to be caused by multidrug-resistant organisms. Prior BSI occurring between the time of HCT and onset of aGVHD-GI and receipt of etanercept for steroid-refractory aGVHD-GI were independently associated with BSI. Eight patients, all with grade IV aGVHD, representing 30.8% of patients with BSI in this subgroup, experienced infection-associated mortality. Cumulative survival at days 30 and 45 after onset of grade IV aGVHD-GI was similar among patients with and without BSI. BSI is a common complication of grade IV aGVHD-GI, resulting in significant infection-associated mortality. Interventions targeting those at highest risk may be warranted.

Amygdalar Gray Matter Volume and Social Relating in Schizophrenia.

BACKGROUND: Poor social relating is a prominent feature of schizophrenia. The amygdala has been suggested as an important node in social brain networks. METHODS: By using structural magnetic resonance imaging, this study examined, for the first time, the relationship between amygdalar gray matter (GM) volume and social relating in 35 schizophrenia patients. Social anhedonia, interaction anxiety, extraversion, and sociable tendencies were assessed as indices of social relating. RESULTS: A correlation between GM volume in the amygdala and enhanced social relating was revealed. CONCLUSION: These findings indicate that volumetric decreases in the amygdala are related to impoverished sociability in schizophrenia.

Automatic amygdala response to facial expression in schizophrenia: initial hyperresponsivity followed by hyporesponsivity.

BACKGROUND: It is well established that the amygdala is crucially involved in the processing of facial emotions. In schizophrenia patients, a number of neuroimaging findings suggest hypoactivation of the amygdala in response to facial emotion, while others indicate normal or enhanced recruitment of this region. Some of this variability may be related to the baseline condition used and the length of the experiment. There is evidence that schizophrenia patients display increased activation of the amygdala to neutral faces and that this is predominantly observed during early parts of the experiment. Recent research examining the automatic processing of facial emotion has also reported amygdala hyperactivation in schizophrenia. In the present study, we focused on the time-course of amygdala activation during the automatic processing of emotional facial expression. We hypothesized that in comparison to healthy subjects, patients would initially show hyperresponsivity of the amygdala to masked emotional and neutral faces. In addition, we expected amygdala deactivation in response to masked facial emotions from the first to the second phase to be more pronounced in patients than in controls. RESULTS: Amygdala activation in response to angry, happy, neutral, and no facial expression (presented for 33 ms) was measured by functional magnetic resonance imaging in 30 schizophrenia patients and 35 healthy controls. Across all subjects, the bilateral amygdala response to faces (relative to the no facial expression condition) was larger in the initial phase (first half of trials) than in the second phase (second half of trials). During the initial phase, schizophrenia patients exhibited an increased right amygdala response to all faces and an increased left amygdala response to neutral faces compared with controls. During the second phase, controls manifested a higher right amygdala response for all faces and a higher left amygdala response to angry faces than patients. CONCLUSIONS: Schizophrenia patients are characterized by high initial amygdala responsivity to facial expressions at an automatic processing level, which substantially decreases with time. Amygdala deactivation over time might reflect an automatic mechanism by which schizophrenia patients suppress the processing of facial stimuli. This blocking mechanism could help patients avoid overstimulation during social interactions.

Brain response to masked and unmasked facial emotions as a function of implicit and explicit personality self-concept of extraversion.

Extraversion-introversion is a personality dimension referring to individual differences in social behavior. In the past, neurobiological research on extraversion was almost entirely based upon questionnaires which inform about the explicit self-concept. Today, indirect measures are available that tap into the implicit self-concept of extraversion which is assumed to result from automatic processing functions. In our study, brain activation while viewing facial expression of affiliation relevant (i.e., happiness, and disgust) and irrelevant (i.e., fear) emotions was examined as a function of the implicit and explicit self-concept of extraversion and processing mode (automatic vs. controlled). 40 healthy volunteers watched blocks of masked and unmasked emotional faces while undergoing functional magnetic resonance imaging. The Implicit Association Test and the NEO Five-Factor Inventory were applied as implicit and explicit measures of extraversion which were uncorrelated in our sample. Implicit extraversion was found to be positively associated with neural response to masked happy faces in the thalamus and temporo-parietal regions and to masked disgust faces in cerebellar areas. Moreover, it was positively correlated with brain response to unmasked disgust faces in the amygdala and cortical areas. Explicit extraversion was not related to brain response to facial emotions when controlling trait anxiety. The implicit compared to the explicit self-concept of extraversion seems to be more strongly associated with brain activation not only during automatic but also during controlled processing of affiliation relevant facial emotions. Enhanced neural response to facial disgust could reflect high sensitivity to signals of interpersonal rejection in extraverts (i.e., individuals with affiliative tendencies).

Methods of fetal MR: beyond T2-weighted imaging.

The present work reviews the basic methods of performing fetal magnetic resonance imaging (MRI). Since fetal MRI differs in many respects from a postnatal study, several factors have to be taken into account to achieve satisfying image quality. Image quality depends on adequate positioning of the pregnant woman in the magnet, use of appropriate coils and the selection of sequences. Ultrafast T2-weighted sequences are regarded as the mainstay of fetal MR-imaging. However, additional sequences, such as T1-weighted images, diffusion-weighted images, echoplanar imaging may provide further information, especially in extra- central-nervous system regions of the fetal body.

Affective Flattening in Patients with Schizophrenia: Differential Association with Amygdala Response to Threat-Related Facial Expression under Automatic and Controlled Processing Conditions.

OBJECTIVE: Early neuroimaging studies have demonstrated amygdala hypoactivation in schizophrenia but more recent research based on paradigms with minimal cognitive loads or examining automatic processing has observed amygdala hyperactivation. Hyperactivation was found to be related to affective flattening. In this study, amygdala responsivity to threat-related facial expression was investigated in patients as a function of automatic versus controlled processing and patients' flat affect. METHODS: Functional magnetic resonance imaging was used to measure amygdala activation in 36 patients with schizophrenia and 42 healthy controls. During scanning, a viewing task with masked and unmasked fearful and neutral faces was presented. RESULTS: Patients exhibited increased amygdala response to unmasked fearful faces. With respect to masked fearful faces, no between-group differences emerged for the sample as a whole but a subsample of patients with flat affect showed heightened amygdala activation. The amygdala response to masked fearful faces was positively correlated with the degree of flat affect. Conversely, amygdala response to unmasked fearful faces was negatively correlated to the severity of affective flattening. In patients, amygdala responses to masked and unmasked fearful faces showed an inverse correlation. CONCLUSION: Our findings suggest that amygdala hyperresponsivity to unmasked fearful faces might be a functional characteristic of schizophrenia. Amygdala hyperresponsivity to masked fearful faces might be a specific characteristic of patients with affective flattening. A model of flat affect as a response mechanism to emotional overload is proposed.

Using implicit association tests for the assessment of implicit personality self-concepts of extraversion and neuroticism in schizophrenia.

There is evidence from research based on self-report personality measures that schizophrenia patients tend to be lower in extraversion and higher in neuroticism than healthy individuals. Self-report personality measures assess aspects of the explicit self-concept. The Implicit Association Test (IAT) has been developed to assess aspects of implicit cognition such as implicit attitudes and implicit personality traits. The present study was conducted to investigate the applicability and reliability of the IAT in schizophrenia patients and test whether they differ from healthy individuals on implicitly measured extraversion and neuroticism. The IAT and the NEO-FFI were administered as implicit and explicit measures of extraversion and neuroticism to 34 schizophrenia patients and 45 healthy subjects. For all IAT scores satisfactory to good reliabilities were observed in the patient sample. In both study groups, IAT scores were not related to NEO-FFI scores. Schizophrenia patients were lower in implicit and explicit extraversion and higher in implicit and explicit neuroticism than healthy individuals. Our data show that the IAT can be reliably applied to schizophrenia patients and suggest that they differ from healthy individuals not only in their conscious representation but also in their implicit representation of the self with regard to neuroticism and extraversion-related characteristics.

Social alienation in schizophrenia patients: association with insula responsiveness to facial expressions of disgust.

INTRODUCTION: Among the functional neuroimaging studies on emotional face processing in schizophrenia, few have used paradigms with facial expressions of disgust. In this study, we investigated whether schizophrenia patients show less insula activation to macro-expressions (overt, clearly visible expressions) and micro-expressions (covert, very brief expressions) of disgust than healthy controls. Furthermore, departing from the assumption that disgust faces signal social rejection, we examined whether perceptual sensitivity to disgust is related to social alienation in patients and controls. We hypothesized that high insula responsiveness to facial disgust predicts social alienation. METHODS: We used functional magnetic resonance imaging to measure insula activation in 36 schizophrenia patients and 40 healthy controls. During scanning, subjects passively viewed covert and overt presentations of disgust and neutral faces. To measure social alienation, a social loneliness scale and an agreeableness scale were administered. RESULTS: Schizophrenia patients exhibited reduced insula activation in response to covert facial expressions of disgust. With respect to macro-expressions of disgust, no between-group differences emerged. In patients, insula responsiveness to covert faces of disgust was positively correlated with social loneliness. Furthermore, patients' insula responsiveness to covert and overt faces of disgust was negatively correlated with agreeableness. In controls, insula responsiveness to covert expressions of disgust correlated negatively with agreeableness. DISCUSSION: Schizophrenia patients show reduced insula responsiveness to micro-expressions but not macro-expressions of disgust compared to healthy controls. In patients, low agreeableness was associated with stronger insula response to micro- and macro-expressions of disgust. Patients with a strong tendency to feel uncomfortable with social interactions appear to be characterized by a high sensitivity for facial expression signaling social rejection. Given the associations of insula responsiveness to covert disgust expression with low agreeableness in healthy individuals, insula responsiveness to expressions of disgust might be in general a neural marker of the personality trait of agreeableness.

Fetal eye movements on magnetic resonance imaging.

OBJECTIVES: Eye movements are the physical expression of upper fetal brainstem function. Our aim was to identify and differentiate specific types of fetal eye movement patterns using dynamic MRI sequences. Their occurrence as well as the presence of conjugated eyeball motion and consistently parallel eyeball position was systematically analyzed. METHODS: Dynamic SSFP sequences were acquired in 72 singleton fetuses (17-40 GW, three age groups [17-23 GW, 24-32 GW, 33-40 GW]). Fetal eye movements were evaluated according to a modified classification originally published by Birnholz (1981): Type 0: no eye movements; Type I: single transient deviations; Type Ia: fast deviation, slower reposition; Type Ib: fast deviation, fast reposition; Type II: single prolonged eye movements; Type III: complex sequences; and Type IV: nystagmoid. RESULTS: In 95.8% of fetuses, the evaluation of eye movements was possible using MRI, with a mean acquisition time of 70 seconds. Due to head motion, 4.2% of the fetuses and 20.1% of all dynamic SSFP sequences were excluded. Eye movements were observed in 45 fetuses (65.2%). Significant differences between the age groups were found for Type I (p = 0.03), Type Ia (p = 0.031), and Type IV eye movements (p = 0.033). Consistently parallel bulbs were found in 27.3-45%. CONCLUSIONS: In human fetuses, different eye movement patterns can be identified and described by MRI in utero. In addition to the originally classified eye movement patterns, a novel subtype has been observed, which apparently characterizes an important step in fetal brainstem development. We evaluated, for the first time, eyeball position in fetuses. Ultimately, the assessment of fetal eye movements by MRI yields the potential to identify early signs of brainstem dysfunction, as encountered in brain malformations such as Chiari II or molar tooth malformations.

ATP-binding cassette transporters in immortalised human brain microvascular endothelial cells in normal and hypoxic conditions.

BACKGROUND: Rapid reperfusion following ischemia is the most effective therapy in stroke therapy. However, the success may be compromised by ischemia & reperfusion (I/R) injury and at the human blood-brain barrier (BBB), therefore the effects on transendothelial transport are of special interest. Current studies suggest the ATP-binding cassette (ABC) transporters to be regulated upon ischemic stroke in a way that impedes the effects of drug therapy. The immortalised human brain microvascular endothelial cell line hCMEC/D3 provides most of the unique properties of the BBB with respect to transport and might be a reliable in vitro model to study transendothelial transport after I/R. METHODS: We exposed hCMEC/D3 cells to 24 hours of hypoxia alone and to hypoxia followed by 60 min of reoxygenisation as an in vitro model for I/R. Western blot showed mild upregulation of hypoxia inducible factor (HIF-1α) after hypoxia alone and RNA lysates were analysed with a well-established real-time RT-PCR-based TaqMan low-density array detecting 47 of 48 known human ABC transporters. RESULTS: No significant increases of ABC mRNA expression levels were detected neither in hypoxic nor in I/R samples. However, slight decrease of ABCC1 in hypoxic and I/R samples and of ABCA10 and ABCD3 in I/R samples was observed. CONCLUSION: Our data suggests that hCMEC/D3 cell line and - at the moment - in vitro models in general are a poor basis for stroke research but may be enhanced by co-culturing more cells of the neurovascular unit inducing an overall ischemic response at the BBB.

High responsivity to threat during the initial stage of perception in repression: a 3 T fMRI study.

Repression designates coping strategies such as avoidance, or denial that aim to shield the organism from threatening stimuli. Derakshan et al. have proposed the vigilance-avoidance theory of repressive coping. It is assumed that repressors have an initial rapid vigilant response triggering physiological responses to threat stimuli. In the following second stage repressors manifest avoidant cognitive biases. Functional magnetic resonance imaging at 3T was used to study neural correlates of repressive coping during the first stages of perception of threat. Pictures of human faces bearing fearful, angry, happy and neutral expressions were briefly presented masked by neutral faces. Forty study participants (20 repressive and 20 sensitizing individuals) were selected from a sample of 150 female students on the basis of their scores on the Mainz Coping Inventory. Repressors exhibited stronger neural activation than sensitizers primarily in response to masked threatening faces (vs neutral baseline) in the frontal, parietal and temporal cortex as well as in the cingulate gyrus, basal ganglia and insula. There was no brain region in which sensitizers showed increased activation to emotion expression compared to repressors. The present results are in line with the vigilance-avoidance theory which predicts heightened automatic responsivity to threatening stimuli in repression.

Limbic scars: long-term consequences of childhood maltreatment revealed by functional and structural magnetic resonance imaging.

BACKGROUND: Childhood maltreatment represents a strong risk factor for the development of depression and posttraumatic stress disorder (PTSD) in later life. In the present study, we investigated the neurobiological underpinnings of this association. Since both depression and PTSD have been associated with increased amygdala responsiveness to negative stimuli as well as reduced hippocampal gray matter volume, we speculated that childhood maltreatment results in similar functional and structural alterations in previously maltreated but healthy adults. METHODS: One hundred forty-eight healthy subjects were enrolled via public notices and newspaper announcements and were carefully screened for psychiatric disorders. Amygdala responsiveness was measured by means of functional magnetic resonance imaging and an emotional face-matching paradigm particularly designed to activate the amygdala in response to threat-related faces. Voxel-based morphometry was used to study morphological alterations. Childhood maltreatment was assessed by the 25-item Childhood Trauma Questionnaire (CTQ). RESULTS: We observed a strong association of CTQ scores with amygdala responsiveness to threat-related facial expressions. The morphometric analysis yielded reduced gray matter volumes in the hippocampus, insula, orbitofrontal cortex, anterior cingulate gyrus, and caudate in subjects with high CTQ scores. Both of these associations were not influenced by trait anxiety, depression level, age, intelligence, education, or more recent stressful life events. CONCLUSIONS: Childhood maltreatment is associated with remarkable functional and structural changes even decades later in adulthood. These changes strongly resemble findings described in depression and PTSD. Therefore, the present results might suggest that limbic hyperresponsiveness and reduced hippocampal volumes could be mediators between the experiences of adversities during childhood and the development of emotional disorders.