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Endothelial cells (ECs) grant access of disseminated cancer cells to distant organs. However, the molecular players regulating the activation of quiescent ECs at the premetastatic niche (PMN) remain elusive. Here, we find that ECs at the PMN coexpress tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) and its cognate death receptor 5 (DR5). Unexpectedly, endothelial TRAIL interacts intracellularly with DR5 to prevent its signaling and preserve a quiescent vascular phenotype. In absence of endothelial TRAIL, DR5 activation induces EC death and nuclear factor κB/p38-dependent EC stickiness, compromising vascular integrity and promoting myeloid cell infiltration, breast cancer cell adhesion, and metastasis. Consistently, both down-regulation of endothelial TRAIL at the PMN by proangiogenic tumor-secreted factors and the presence of the endogenous TRAIL inhibitors decoy receptor 1 (DcR1) and DcR2 favor metastasis. This study discloses an intracrine mechanism whereby TRAIL blocks DR5 signaling in quiescent endothelia, acting as gatekeeper of the vascular barrier that is corrupted by the tumor during cancer cell dissemination.

Normal Pressure Hydrocephalus due to idiopathic aqueductal stenosis is a chronic abnormal accumulation of cerebrospinal fluid in the cerebral ventricles caused by an obstruction in the Sylvian aqueduct. This leads to a dilatation of the ventricular system and to subsequent damage of the adjacent parenchyma. Although NPH typically presents with the progressive 'triad' of cognitive impairment, gait disturbance and urinary incontinence, it has been described that it rarely manifests in the form of predominant psychotic symptoms. It has been suggested that thought and perceptual disorders could develop secondary to the damage caused by NPH. Although precise anatomical correlates have not yet been established, certain cerebral regions -primarily the frontal cortex, mesencephalic and diencephalic structures of the brain- have been implicated in the pathogenesis of hydrocephalic psychosis. Because frontal lobe lesions are traditionally known to facilitate one's inability to integrate and correct perceptual distortions in the face of contradictory evidence, frontal lobe dysfunction may be integral in delineating the etiology of delusions in NPH. We present the case of a 30-year-old female, admitted involuntarily to our acute psychiatric department because she exhibited aggressive behavior while being in an agitated state with delusions of persecution. Her neurological examination disclosed subtle bradykinesia. Neuropsychological batteries and intelligence testing revealed mild cognitive impairment and a CT scan showed considerable dilatation of the ventricular system due to idiopathic aqueductal stenosis. While a conservative approach was chosen for the treatment of NPH, our patient was initiated on 2nd generation antipsychotics showing marked improvement of her psychiatric symptomatology. The atypical presentation of hydrocephalus in the aforementioned case underlines the necessity to thoroughly investigate the possible presence of an underlying organic factor in those patients who present with predominant psychotic symptoms in association with soft non-localising neurological signs and mild cognitive deficits. Furthermore, our patient's marked improvement indicates that, in cases where the primary cause is treated conservatively, hydrocephalic psychosis could respond to 2nd generation antipsychotics. In light of this case report, we reviewed past and present literature on the matter.

A male patient aged 43 presented with psychotic symptomatology after a traumatic event involving accidental mutilation of the fingers. Initial presentation was uncommon although the patient responded well to pharmacotherapy. The theoretical framework, management plan and details of the treatment are presented.