Many studies have suggested that childhood maltreatment increase risk of adulthood major depressive disorder (MDD) and predict its unfavorable treatment outcome, yet the neural underpinnings associated with childhood maltreatment in MDD remain poorly understood. Here, we seek to investigate the whole-brain functional connectivity patterns in MDD patients with childhood maltreatment. Resting-state functional magnetic resonance imaging was used to explore intrinsic or spontaneous functional connectivity networks of 18 MDD patients with childhood neglect, 20 MDD patients without childhood neglect, and 20 healthy controls. Whole-brain functional networks were constructed by measuring the temporal correlations of every pairs of brain voxels and were further analyzed by using graph-theory approaches. Relative to the healthy control group, the two MDD patient groups showed overlapping reduced functional connectivity strength in bilateral ventral medial prefrontal cortex/ventral anterior cingulate cortex. However, compared with MDD patients without a history of childhood maltreatment, those patients with such a history displayed widespread reduction of functional connectivity strength primarily in brain regions within the prefrontal-limbic-thalamic-cerebellar circuitry, and these reductions significantly correlated with measures of childhood neglect. Together, we showed that the MDD groups with and without childhood neglect exhibited overlapping and segregated functional connectivity patterns in the whole-brain networks, providing empirical evidence for the contribution of early life stress to the pathophysiology of MDD.

SUMMARY Plasminogen activator inhibitor-1 (PAI-1) paradoxically enhances tumor progression and angiogenesis, however the mechanism supporting this role is not known. Here we provide evidence that PAI-1 is essential to protect endothelial cells (EC) from FasL-mediated apoptosis. In the absence of host-derived PAI-1, human neuroblastoma cells implanted in PAI-1 deficient mice form smaller and poorly vascularized tumors containing an increased number of apoptotic EC cells. We observed that knockdown of PAI-1 in EC enhances cell-associated plasmin activity, and increases spontaneous apoptosis in vitro. We further demonstrate that plasmin cleaves FasL at Arg144 - Lys145, releasing from the surface of EC a soluble pro-apoptotic FasL fragment. The data provide a mechanism explaining the pro-angiogenic activity of PAI-1. SIGNIFICANCE PAI-1, the central regulator of plasmin generation is a predictor of poor clinical outcome in cancer patients. We previously reported that PAI-1 has a pro-angiogenic function but the mechanism has remained poorly understood. Here we describe a mechanism for the pro-angiogenic function of PAI-1 by providing evidence that PAI-1 protects EC from Fas/FasL-mediated apoptosis. We demonstrate that in the absence of PAI-1 in EC, there is an increase in plasmin generation and the release by plasmin of a soluble FasL fragment. This plasmin-generated soluble FasL activates Fas and is a potent inducer of apoptosis in EC. Our results suggest that PAI-1 could be a target for anti-angiogenic and anti-vascular therapies.

No abstract

No abstract

No abstract

Supplemental Digital Content is available in the text

Major depressive disorder (MDD) is one of the most prevalent mental disorders. In the brain, the hubs of the brain network play a key role in integrating and transferring information between different functional modules. However, whether the changed pattern in functional network hubs contributes to the onset of MDD remains unclear. Using resting-state functional magnetic resonance imaging (rs-fMRI) and graph theory methods, we investigated whether alterations of hubs can be detected in MDD. First, we constructed the whole-brain voxel-wise functional networks and calculated a functional connectivity strength (FCS) map in each subject in 34 MDD patients and 34 gender-, age- and education level-matched healthy controls (HCs). Next, the two-sample t-test was applied to compare the FCS maps between HC and MDD patients and identified significant decrease of FCS in subgenual anterior cingulate cortex (sgACC) in MDD patients. Subsequent functional connectivity analyses of sgACC showed disruptions in functional connectivity with posterior insula, middle and inferior temporal gyrus, lingual gyrus and cerebellum in MDD patients. Furthermore, the changed FCS of sgACC and functional connections to sgACC were significantly correlated with the Hamilton Depression Rating Scale (HDRS) scores in MDD patients. The results of the present study revealed the abnormal hub of sgACC and its corresponding disrupted frontal-limbic-visual cognitive-cerebellum functional networks in MDD. These findings may provide a new insight for the diagnosis and treatment of MDD.

BackgroundThe 32-item Hypomania Checklist (HCL-32), a questionnaire for screening bipolar disorders, has been utilised in several countries, but it unclear if the Chinese version of the HCL-32 is valid.MethodsConsecutive patients with bipolar disorders (BP, N = 300) and unipolar major depression (UP, N = 156) completed the Chinese version of the HCL-32. The subjects underwent a structured clinical interview for DSM-IV Axis-I disorders (SCID).ResultsThe eigenvalues for the first three factors in the HCL-32 were calculated as 5.16 (active/elated), 2.72 (risk-taking) and 2.48 (irritable) using factor analysis. Cronbach's alpha for the HCL-32 was calculated to be 0.88. Positive responses to twenty-eight items were significantly more frequent by patients with BP than those with UP, and the other four items (7th, 21st, 25th and 32nd) showed no such trend. Fourteen was the optimal cut-off for discriminating between BP and UP. The HCL-32 distinguished between BP-II and UP, with 13 being the optimal cut-off. A cut-off of 13 yielded a sensitivity of 0.77 and a specificity of 0.62 between BP and UP.ConclusionsThis study demonstrated that the simplified Chinese version of HCL-32 was valid for patients with mood disorders. The optimal cut-off of 13 for distinguishing between BP-II and UP was valid and could be used to improve the sensitivity of screening BP-II patients when the HCL-32 is used in psychiatric settings in China.