Childhood Adversity Is Associated with Adult Theory of Mind and Social Affiliation,but Not Face Processing

People vary substantially in their ability to acquire and maintain social ties. Here, we use a combined epidemiological and individual differences approach to understand the childhood roots of adult social cognitive functioning. We assessed exposure to 25 forms of traumatic childhood experiences in over 5000 adults, along with measures of face discrimination, face memory, theory of mind, social motivation, and social support. Retrospectively-reported experiences of parental maltreatment in childhood (particularly physical abuse) were the most broadly and robustly associated with adult variations in theory of mind, social motivation, and social support. Adult variations in face discrimination and face memory, on the other hand, were not significantly associated with exposure to childhood adversity. Our findings indicate domains of social cognition that may be particularly vulnerable to the effects of adverse childhood environments, and suggest mechanisms whereby environmental factors might influence the development of social abilities.     

Suppression of Graft Regeneration,Not Ischemia/Reperfusion Injury,Is the Primary Cause of Small-for-Size Syndrome after Partial Liver Transplantation in Mice

Background

Ischemia/reperfusion injury (IRI) is commonly considered to play a crucial role in the pathogenesis of small-for-size syndrome (SFSS) after liver transplantation. Rapid regeneration is also considered essential for the survival of SFS grafts.

Methods

Mouse models of full-size orthotopic liver transplantation, 50% partial liver transplantation and 30% partial liver transplantation were established. Survival rate and serum alanine aminotransferase were observed. IRI was assessed by hepatic pathologic alterations, apoptosis and necrosis. Regeneration response was detected by mitotic index, BrdU incorporation and PCNA, Cyclin D1 and Cyclin E expression. The expression of mTOR, AKT, ERK, JNK2 and p70S6K, also involved in regeneration signaling pathways, were analyzed as well.

Results

30% partial liver graft resulted in a significantly low 7-day survival rate (P = 0.002) with no marked difference in tissue injury compared with the 50% partial graft group. Serum alanine aminotransferase levels were not significantly different between partial transplantation and full-size transplantation. Western blot analysis of caspase-3 and TUNEL staining also indicated no significant difference in apoptosis response between 30% partial transplantation and half-size or full-size transplantation (P = 0.436, P = 0.113, respectively). However, liver regeneration response indicators, mitotic index (P<0.0001) and BrdU (P = 0.0022), were markedly lower in 30% LTx compared with 50% LTx. Suppressed expression of PCNA, cyclin D1, cyclin E, mTOR, JNK2, AKT, ERK and p70S6K was also detected by western blot.

Conclusions

Liver regeneration is markedly suppressed in SFSS, and is more likely the primary cause of SFSS, rather than ischemia/reperfusion injury. Therapy for recovering graft regeneration could be a potentially important strategy to reduce the incidence of SFSS.     

Pre-Transplant Depression Is Associated with Length of Hospitalization,Discharge Disposition,and Survival after Liver Transplantation

Depression after liver transplantation has been associated with decreased survival, but the effects of pre-transplant depression on early and late post-transplant outcomes remain incompletely evaluated. We assessed all patients who had undergone single-organ liver transplantation at a single center over the prior 10 years. A diagnosis of pre-transplant depression, covariates, and the outcomes of interest were extracted from the electronic medical record. Potential covariates included demographics, etiology and severity of liver disease, comorbidities, donor age, graft type, immunosuppression, and ischemic times. In multivariable models adjusting for these factors, we evaluated the effect of pre-transplant depression on transplant length of stay (LOS), discharge disposition (home vs. facility) and long-term survival. Among 1115 transplant recipients with a median follow-up time of 5 years, the average age was 56±11 and MELD was 12±9. Nineteen percent of the study population had a history of pre-transplant depression. Pre-transplant depression was associated with longer LOS (median = 19 vs. 14 days, IRR = 1.25, CI = 1.13,1.39), discharge to a facility (36% vs. 25%, OR 1.70,CI = 1.18,2.45), and decreased survival (HR = 1.54,CI = 1.14,2.08) in this cohort, accounting for other potential confounders. In conclusion, pre-transplant depression was significantly associated with longer transplant length of stay, discharge to a facility, and mortality in this cohort.     

Glutamatergic Neurotransmission from Melanopsin Retinal Ganglion Cells Is Required for Neonatal Photoaversion but Not Adult Pupillary Light Reflex

Melanopsin-expressing retinal ganglion cells (mRGCs) in the eye play an important role in many light-activated non-image-forming functions including neonatal photoaversion and the adult pupillary light reflex (PLR). MRGCs rely on glutamate and possibly PACAP (pituitary adenylate cyclase-activating polypeptide) to relay visual signals to the brain. However, the role of these neurotransmitters for individual non-image-forming responses remains poorly understood. To clarify the role of glutamatergic signaling from mRGCs in neonatal aversion to light and in adult PLR, we conditionally deleted vesicular glutamate transporter (VGLUT2) selectively from mRGCs in mice. We found that deletion of VGLUT2 in mRGCs abolished negative phototaxis and light-induced distress vocalizations in neonatal mice, underscoring a necessary role for glutamatergic signaling. In adult mice, loss of VGLUT2 in mRGCs resulted in a slow and an incomplete PLR. We conclude that glutamatergic neurotransmission from mRGCs is required for neonatal photoaversion but is complemented by another non-glutamatergic signaling mechanism for the pupillary light reflex in adult mice. We speculate that this complementary signaling might be due to PACAP neurotransmission from mRGCs.     

ADF/Cofilin Is Not Essential but Is Critically Important for Actin Activities during Phagocytosis in Tetrahymena thermophila

ADF/cofilin is a highly conserved actin-modulating protein. Reorganization of the actin cytoskeleton in vivo through severing and depolymerizing of F-actin by this protein is essential for various cellular events, such as endocytosis, phagocytosis, cytokinesis, and cell migration. We show that in the ciliate Tetrahymena thermophila, the ADF/cofilin homologue Adf73p associates with actin on nascent food vacuoles. Overexpression of Adf73p disrupted the proper localization of actin and inhibited the formation of food vacuoles. In vitro, recombinant Adf73p promoted the depolymerization of filaments made of T. thermophila actin (Act1p). Knockout cells lacking the ADF73 gene are viable but grow extremely slowly and have a severely decreased rate of food vacuole formation. Knockout cells have abnormal aggregates of actin in the cytoplasm. Surprisingly, unlike the case in animals and yeasts, in Tetrahymena, ADF/cofilin is not required for cytokinesis. Thus, the Tetrahymena model shows promise for future studies of the role of ADF/cofilin in vivo.     

The PhysioFlow Thoracic Impedancemeter Is Not Valid for the Measurements of Cardiac Hemodynamic Parameters in Chronic Anemic Patients

The aim of the present study was to test the validity of the transthoracic electrical bioimpedance method PhysioFlow® to measure stroke volume in patients with chronic anemia. Stroke volume index (SVI), as well as cardiac index (CI) obtained by transthoracic electrical bioimpedance method and doppler echocardiography were compared in healthy subjects (n = 25) and patients with chronic anemia (i.e. mainly with sickle cell anemia; n = 32), at rest. While doppler echocardiography was able to detect difference in SVI between the two populations, the Physioflow® failed to detect any difference. Bland & Altman analyses have demonstrated no interchangeability between the two methods to assess CI and SVI in anemic patients and healthy subjects. While doppler echocardiography displayed a good concordance for SVI results with those obtained in the literature for anemic patients, the Physioflow® did not. Finally, in contrast to doppler echocardiography: 1) the CI obtained with the Physioflow® was not correlated with the hemoglobin level and 2) the stroke volume determined by the Physioflow® was highly influenced by body surface area. In conclusion, our findings indicate that the Physioflow® device is inaccurate for the measurement of SVI and CI in patients with chronic anemia and has a poor accuracy for the measurement of these parameters in African healthy subjects.     

Erbb2 Is Required for Cardiac Atrial Electrical Activity during Development

The heart is the first organ required to function during embryonic development and is absolutely necessary for embryo survival. Cardiac activity is dependent on both the sinoatrial node (SAN), which is the pacemaker of heart''s electrical activity, and the cardiac conduction system which transduces the electrical signal though the heart tissue, leading to heart muscle contractions. Defects in the development of cardiac electrical function may lead to severe heart disorders. The Erbb2 (Epidermal Growth Factor Receptor 2) gene encodes a member of the EGF receptor family of receptor tyrosine kinases. The Erbb2 receptor lacks ligand-binding activity but forms heterodimers with other EGF receptors, stabilising their ligand binding and enhancing kinase-mediated activation of downstream signalling pathways. Erbb2 is absolutely necessary in normal embryonic development and homozygous mouse knock-out Erbb2 embryos die at embryonic day (E)10.5 due to severe cardiac defects. We have isolated a mouse line, l11Jus8, from a random chemical mutagenesis screen, which carries a hypomorphic missense mutation in the Erbb2 gene. Homozygous mutant embryos exhibit embryonic lethality by E12.5-13. The l11Jus8 mutants display cardiac haemorrhage and a failure of atrial function due to defects in atrial electrical signal propagation, leading to an atrial-specific conduction block, which does not affect ventricular conduction. The l11Jus8 mutant phenotype is distinct from those reported for Erbb2 knockout mouse mutants. Thus, the l11Jus8 mouse reveals a novel function of Erbb2 during atrial conduction system development, which when disrupted causes death at mid-gestation.     

Access to Awareness for Faces during Continuous Flash Suppression Is Not Modulated by Affective Knowledge

It is a controversially debated topic whether stimuli can be analyzed up to the semantic level when they are suppressed from visual awareness during continuous flash suppression (CFS). Here, we investigated whether affective knowledge, i.e., affective biographical information about faces, influences the time it takes for initially invisible faces with neutral expressions to overcome suppression and break into consciousness. To test this, we used negative, positive, and neutral famous faces as well as initially unfamiliar faces, which were associated with negative, positive or neutral biographical information. Affective knowledge influenced ratings of facial expressions, corroborating recent evidence and indicating the success of our affective learning paradigm. Furthermore, we replicated shorter suppression durations for upright than for inverted faces, demonstrating the suitability of our CFS paradigm. However, affective biographical information did not modulate suppression durations for newly learned faces, and even though suppression durations for famous faces were influenced by affective knowledge, these effects did not differ between upright and inverted faces, indicating that they might have been due to low-level visual differences. Thus, we did not obtain unequivocal evidence for genuine influences of affective biographical information on access to visual awareness for faces during CFS.     

Fibroblast Growth Factor 10-Fibroblast Growth Factor Receptor 2b Mediated Signaling Is Not Required for Adult Glandular Stomach Homeostasis

The signaling pathways that are essential for gastric organogenesis have been studied in some detail; however, those that regulate the maintenance of the gastric epithelium during adult homeostasis remain unclear. In this study, we investigated the role of Fibroblast growth factor 10 (FGF10) and its main receptor, Fibroblast growth factor receptor 2b (FGFR2b), in adult glandular stomach homeostasis. We first showed that mouse adult glandular stomach expressed Fgf10, its receptors, Fgfr1b and Fgfr2b, and most of the other FGFR2b ligands (Fgf1, Fgf7, Fgf22) except for Fgf3 and Fgf20. Fgf10 expression was mesenchymal whereas FGFR1 and FGFR2 expression were mostly epithelial. Studying double transgenic mice that allow inducible overexpression of Fgf10 in adult mice, we showed that Fgf10 overexpression in normal adult glandular stomach increased epithelial proliferation, drove mucous neck cell differentiation, and reduced parietal and chief cell differentiation. Although a similar phenotype can be associated with the development of metaplasia, we found that Fgf10 overexpression for a short duration does not cause metaplasia. Finally, investigating double transgenic mice that allow the expression of a soluble form of Fgfr2b, FGF10''s main receptor, which acts as a dominant negative, we found no significant changes in gastric epithelial proliferation or differentiation in the mutants. Our work provides evidence, for the first time, that the FGF10-FGFR2b signaling pathway is not required for epithelial proliferation and differentiation during adult glandular stomach homeostasis.     

Development of a New Technique for Reconstruction of Hepatic Artery during Liver Transplantation in Sprague-Dawley Rat

Background

Sleeve anastomosis is the most common technique used to rearterialize orthotopic liver transplants (OLT). However, this technique has a number of disadvantages, including difficulty of performance of the technique visually unaided. We herein describe a novel rearterialized OLT model in the rat.

Materials and Methods

Forty-six male Sprague Dawley rats (300–400 g) were used as donors and recipients. Based on Kamada’s cuff technique, the new model involved performing a modified “sleeve” anastomosis between the celiac trunk of the donor and common hepatic artery of the recipient to reconstruct blood flow to the hepatic artery. An additional ten male Sprague Dawley rats underwent liver transplantation without artery reconstruction. Liver grafts were retrieved from the two groups and histological examination was performed following surgery.

Results

Total mean operating times were ~42 minutes for the donor liver extraction and 57 minutes for the recipient transplantation. Graft preparation took an additional 15 minutes and the time to fix the arterial bracket was ~3 minutes. During transplantation, the anhepatic phase lasted 18 ± 2.5 min and the artery reconstruction only required ~3 minutes. The patency rate was 94.44% and the 4-week survival rate was 90%. Histology indicated obvious fibrosis in the liver grafts without artery reconstruction, while normal histology was observed in the arterialized graft.

Conclusions

This new method allows for the surgical procedure to be performed visually unaided with good survival and patency rates and represents an alternative model investigating OLT in rats.     

早期康复训练及自理能力监测表在肝移植患者术后康复中的应用

目的:研究早期康复训练及监测患者自理能力对肝移植术后康复的影响。方法:选择2011年5月至2012年6月在我院接受肝移植手术的患者60例,按手术先后进行编号,使用随机排列表将患者分为实验组和对照组,每组各30例,对照组应用常规术后宣教和护理模式,室验组应用有针对性的"肝移植术后早期康复训练计划",并采用"自理能力监测表"对患者进行评估。分别比较两组患者的术后康复情况、睡眠和疼痛情况、术后第十日的自理能力以及术后早期并发症的发生。结果:两组患者康复情况比较,首次排气、排便、拔除尿管后首次排尿、首次下床和出院时间都有统计学差异(P0.05)。患者睡眠和疼痛情况比较,患者每日睡眠时间增加,安眠药物使用率明显减少(P0.05),而且术后康复训练没有增加患者术后疼痛的发生。术后第十日的自理能力比较,除自行进食(P0.05)外,自主上下床、自主如厕和自主洗漱三个方面室验组明显比对照组好(P0.05)。两组患者术后早期并发症的发生均无统计学差异(P0.05)。结论:早期康复训练和自理能力监测能有效促进肝移植术后患者的康复进程。     

The EF-hand Ca2+ Binding Domain Is Not Required for Cytosolic Ca2+ Activation of the Cardiac Ryanodine Receptor

Activation of the cardiac ryanodine receptor (RyR2) by elevating cytosolic Ca²⁺ is a central step in the process of Ca²⁺-induced Ca²⁺ release, but the molecular basis of RyR2 activation by cytosolic Ca²⁺ is poorly defined. It has been proposed recently that the putative Ca²⁺ binding domain encompassing a pair of EF-hand motifs (EF1 and EF2) in the skeletal muscle ryanodine receptor (RyR1) functions as a Ca²⁺ sensor that regulates the gating of RyR1. Although the role of the EF-hand domain in RyR1 function has been studied extensively, little is known about the functional significance of the corresponding EF-hand domain in RyR2. Here we investigate the effect of mutations in the EF-hand motifs on the Ca²⁺ activation of RyR2. We found that mutations in the EF-hand motifs or deletion of the entire EF-hand domain did not affect the Ca²⁺-dependent activation of [³H]ryanodine binding or the cytosolic Ca²⁺ activation of RyR2. On the other hand, deletion of the EF-hand domain markedly suppressed the luminal Ca²⁺ activation of RyR2 and spontaneous Ca²⁺ release in HEK293 cells during store Ca²⁺ overload or store overload-induced Ca²⁺ release (SOICR). Furthermore, mutations in the EF2 motif, but not EF1 motif, of RyR2 raised the threshold for SOICR termination, whereas deletion of the EF-hand domain of RyR2 increased both the activation and termination thresholds for SOICR. These results indicate that, although the EF-hand domain is not required for RyR2 activation by cytosolic Ca²⁺, it plays an important role in luminal Ca²⁺ activation and SOICR.     

Physical Demand but Not Dexterity Is Associated with Motor Flexibility during Rapid Reaching in Healthy Young Adults

Healthy humans are able to place light and heavy objects in small and large target locations with remarkable accuracy. Here we examine how dexterity demand and physical demand affect flexibility in joint coordination and end-effector kinematics when healthy young adults perform an upper extremity reaching task. We manipulated dexterity demand by changing target size and physical demand by increasing external resistance to reaching. Uncontrolled manifold analysis was used to decompose variability in joint coordination patterns into variability stabilizing the end-effector and variability de-stabilizing the end-effector during reaching. Our results demonstrate a proportional increase in stabilizing and de-stabilizing variability without a change in the ratio of the two variability components as physical demands increase. We interpret this finding in the context of previous studies showing that sensorimotor noise increases with increasing physical demands. We propose that the larger de-stabilizing variability as a function of physical demand originated from larger sensorimotor noise in the neuromuscular system. The larger stabilizing variability with larger physical demands is a strategy employed by the neuromuscular system to counter the de-stabilizing variability so that performance stability is maintained. Our findings have practical implications for improving the effectiveness of movement therapy in a wide range of patient groups, maintaining upper extremity function in old adults, and for maximizing athletic performance.     

MRI Evidence: Acute Mountain Sickness Is Not Associated with Cerebral Edema Formation during Simulated High Altitude

Acute mountain sickness (AMS) is a common condition among non-acclimatized individuals ascending to high altitude. However, the underlying mechanisms causing the symptoms of AMS are still unknown. It has been suggested that AMS is a mild form of high-altitude cerebral edema both sharing a common pathophysiological mechanism. We hypothesized that brain swelling and consequently AMS development is more pronounced when subjects exercise in hypoxia compared to resting conditions. Twenty males were studied before and after an eight hour passive (PHE) and active (plus exercise) hypoxic exposure (AHE) (F_iO₂ = 11.0%, P_iO₂∼80 mmHg). Cerebral edema formation was investigated with a 1.5 Tesla magnetic resonance scanner and analyzed by voxel based morphometry (VBM), AMS was assessed using the Lake Louise Score. During PHE and AHE AMS was diagnosed in 50% and 70% of participants, respectively (p>0.05). While PHE slightly increased gray and white matter volume and the apparent diffusion coefficient, these changes were clearly more pronounced during AHE but were unrelated to AMS. In conclusion, our findings indicate that rest and especially exercise in normobaric hypoxia are associated with accumulation of water in the extracellular space, however independent of AMS development. Thus, it is suggested that AMS and HACE do not share a common pathophysiological mechanism.     

Patterns and Outcomes Associated with Patient Migration for Liver Transplantation in the United States

Background

Traveling to seek specialized care such as liver transplantation (LT) is a reality in the United States. Patient migration has been attributed to organ availability. The aims of this study were to delineate patterns of patient migration and outcomes after LT.

Study Design

All deceased donor LT between 2008–2013 were extracted from UNOS data. Migrated patients were defined as those patients who underwent LT at a center in a different UNOS region from the region in which they resided and traveled a distance > 100 miles.

Results

Migrated patients comprised 8.2% of 28,700 LT performed. Efflux and influx of patients were observed in all 11 UNOS regions. Regions 1, 5, 6, and 9 had a net efflux, while regions 2, 3, 4, 7, 10, and 11 had a net influx of patients. After multivariate adjustment for donor and recipient factors, graft (p = 0.68) and patient survival (p = 0.52) were similar between migrated and non-migrated patients.

Conclusion

A significant number of patients migrated in patterns that could not be explained alone by regional variations in MELD score and wait time. Migration may be a complex interplay of factors including referral patterns, specialized services at centers of excellence and patient preference.     

Temporal but Not Spatial Variability during Gait Is Reduced after Selective Dorsal Rhizotomy in Children with Cerebral Palsy

Introduction

Variability in task output is a ubiquitous characteristic that results from non-continuous motor neuron firing during muscular force generation. However, variability can also be attributed to errors in control and coordination of the motor neurons themselves in diseases such as cerebral palsy (CP). Selective dorsal rhizotomy (SDR), a neurosurgical approach to sever sensory nerve roots, is thought to decrease redundant or excessive afferent signalling to intramedullary neurons. In addition to its demonstrated ability to reduce muscular spasticity, we hypothesised that SDR is able to decrease variability during gait, the most frequent functional motor activity of daily living.

Methods

Twelve CP children (aged 6.1±1.3yrs), who underwent SDR and performed gait analysis pre- and 12 months postoperatively, were compared to a control group of eleven typically developing (TD) children. Coefficients of variability as well as mean values were analysed for: temporal variables of gait, spatial parameters and velocity.

Results

Gait parameters of cadence (p = 0.006) and foot progression angle at mid-stance (p = 0.041) changed significantly from pre- to post-SDR. The variability of every temporal parameter was significantly reduced after SDR (p = 0.003–0.049), while it remained generally unchanged for the spatial parameters. Only a small change in gait velocity was observed, but variability in cadence was significantly reduced after SDR (p = 0.015). Almost all parameters changed with a tendency towards normal, but differences between TD and CP children remained in all parameters.

Discussion

The results confirm that SDR improves functional gait performance in children with CP. However, almost exclusively, parameters of temporal variability were significantly improved, leading to the conjecture that temporal variability and spatial variability may be governed independently by the motor cortex. As a result, temporal parameters of task performance may be more vulnerable to disruption, but also more responsive to treatment success of interventions such as SDR.     

The Ratio of Circulating Regulatory T Cells (Tregs)/Th17 Cells Is Associated with Acute Allograft Rejection in Liver Transplantation

CD4⁺CD25⁺FoxP3⁺ regulatory T cells (Tregs) and Th17 cells are known to be involved in the alloreactive responses in organ transplantation, but little is known about the relationship between Tregs and Th17 cells in the context of liver alloresponse. Here, we investigated whether the circulating Tregs/Th17 ratio is associated with acute allograft rejection in liver transplantation. In present study, thirty-eight patients who received liver transplant were enrolled. The patients were divided into two groups: acute allograft rejection group (Gr-AR) (n = 16) and stable allograft liver function group (Gr-SF) (n = 22). The frequencies of circulating Tregs and circulating Th17 cells, as well as Tregs/Th17 ratio were determined using flow cytometry. The association between Tregs/Th17 ratio and acute allograft rejection was then analyzed. Our results showed that the frequency of circulating Tregs was significantly decreased, whereas the frequency of circulating Th17 cells was significantly increased in liver allograft recipients who developed acute rejection. Tregs/Th17 ratio had a negative correlation with liver damage indices and the score of rejection activity index (RAI) after liver transplantation. In addition, the percentages of CTLA-4⁺, HLA-DR⁺, Ki67⁺, and IL-10⁺ Tregs were higher in Gr-SF group than in Gr-AR group. Our results suggested that the ratio of circulating Tregs/Th17 cells is associated with acute allograft rejection, thus the ratio may serve as an alternative marker for the diagnosis of acute rejection.