Phosphatidylcholine restores neuronal plasticity of neural stem cells under inflammatory stress

The balances between NSCs growth and differentiation, and between glial and neuronal differentiation play a key role in brain regeneration after any pathological conditions. It is well known that the nervous tissue shows a poor recovery after injury due to the factors present in the wounded microenvironment, particularly inflammatory factors, that prevent neuronal differentiation. Thus, it is essential to generate a favourable condition for NSCs and conduct them to differentiate towards functional neurons. Here, we show that neuroinflammation has no effect on NSCs proliferation but induces an aberrant neuronal differentiation that gives rise to dystrophic, non-functional neurons. This is perhaps the initial step of brain failure associated to many neurological disorders. Interestingly, we demonstrate that phosphatidylcholine (PtdCho)-enriched media enhances neuronal differentiation even under inflammatory stress by modifying the commitment of post-mitotic cells. The pro-neurogenic effect of PtdCho increases the population of healthy normal neurons. In addition, we provide evidences that this phospholipid ameliorates the damage of neurons and, in consequence, modulates neuronal plasticity. These results contribute to our understanding of NSCs behaviour under inflammatory conditions, opening up new venues to improve neurogenic capacity in the brain.

Effect of Inflammatory Stress on Neural Stem Cells Behaviour: A Rescue Effect of Phosphatidylcholine by Modulating Neuronal Plasticity.

The balances between NSCs growth and differentiation, and between glial and neuronal differentiation play a key role for brain regeneration after any pathological conditions. It is well known that the nervous tissue shows a poor recovery after injury due to the factors present in the wounded microenvironment, particularly inflammatory factors, that prevent neuronal differentiation. Thus, it is essential to generate a favourable condition for NSCs and conduct them to differentiate towards functional neurons. Here, we show that neuroinflammation has no effect on NSCs proliferation but induces an aberrant neuronal differentiation that gives rise to dystrophic, non-functional neurons. This is perhaps the initial step of brain failure associate to many neurological disorders. Interestingly, we demonstrate that phosphatidylcholine (PtdCho)-enriched media enhances neuronal differentiation even under inflammatory stress by modifying the commitment of post-mitotic cells. The pro-neurogenic effect of PtdCho increases the population of healthy normal neurons. In addition, we provide evidences that this phospholipid ameliorates the damage of neurons and, in consequence, modulates neuronal plasticity. These results contribute to our understanding of NSCs behaviour under inflammatory conditions, opening up new venues to improve neurogenic capacity in the brain.

GUNSHOT WOUND TO THE NECK WITH THROMBOSIS OF THE COMMON CAROTID ARTERY IN THE DELAYED PERIOD. (ANALYSIS OF CLINICAL OBSERVATION)

A case of non-penetrating neck injury with contusion and dissection of the common carotid artery with transition to the internal carotid artery is presented in a clinical observation. The clinical picture of the development of brain failure after thrombosis of the common and internal carotid arteries and regression of brain symptoms after reconstructive surgery is presented. A mathematical model of the lesion mechanism is analyzed separately. It is concluded that in case of a nonpenetrating wound of the neck with a traumatic weapon, the revision of the underlying tissues should be mandatory.

Heterogeneity of HER2 expression in circulating tumor cells of patients with breast cancer brain metastases and impact on brain disease control.

2029 Background: The HER2 expression switching in circulating tumor cells (CTC) of breast cancer is dynamic and may have prognostic and predictive clinical implications. This study aims to analyse the association between expression of HER2 in CTC of patients with breast cancer brain metastases (BCBM) and brain disease control. Methods: Exploratory analysis of a prospective assessment (NCT02941536) of CTC before (CTC1) and 4–5 weeks after (CTC2) stereotactic radiotherapy/radiosurgery (SRT). CTC were isolated and quantified by a method of isolation by size of tumors and analyzed by immunocytochemistry to evaluate the expression of HER2. Distant brain failure-free survival (DBFFS), the primary endpoint, and overall survival (OS) were estimated by Kaplan-Meier estimator. Log-rank tests were applied in order to compare the survival curves. For multivariate analysis of prognostic factors that affected DBFFS and OS, the Cox proportional model was adjusted. Results: The median age at SRT was 54 (34-70), the diagnosis-specific graded prognostic assessment (DS-GPA) was 1–2 in 17.5% and 2.5–4 in 82.5% and the primary immunophenotype (PIP) was HER2-enriched in 51%, luminal B (LB) in 31% and triple negative (TN) in 18% of the total of 39 patients. CTC were detected in all 39 patients before SRT and the median CTC1 was 2 CTC/mL. After SRT, CTC were detected in 34 of 35 patients (4 deaths between CTC1 and CTC2) and the median CTC2 was 2.33 CTC/mL. HER2 was expressed in CTC1 and/or CTC2 in 9 patients, of which only 2 patients had PIP HER2-enriched. After a median follow-up of 16.6 months, there were 15 patients with distant brain failure and 16 deaths. The median DBFFS and OS were 15.3 and 19.5 months, respectively. Median DBFFS was 7 months in patients with PIP TN and was not reached in PIP LB and HER2-enriched (p = 0.036); 14 months in patients with DS-GPA 1-2 and 7 months with DS-GPA 2.5-4 (p = 0.017); 10 months in patients without HER2 expressed in CTC and not reached in patients with HER2 expressed in CTC (p = 0.012). Median OS was 4.8 months in patients with PIP TN and was not reached in PIP LB and HER2-enriched (p = 0.0026); 19.54 months in patients with DS-GPA 1-2 and 7.6 months with DS-GPA 2.5-4 (p = 0.00088); 17 months in patients without HER2 expressed in CTC and not reached in patients with HER2 expressed in CTC (p = 0.104). On multivariate analysis, DBFFS was superior in patients with PIP HER2-enriched (HR 0.128, 95% CI 0.025–0.534; p = 0.013) and OS was superior in patients with PIP HER2-enriched (HR 0.073, 95% CI 0.018-0.288; p < 0.0001) and LB (HR 0.224, 95% CI 0.062–0.816; p = 0.023). The status of expression of HER2 in CTC was not included in Cox model for DBFFS due to lack of events in patients with HER2 expressed in CTC. Conclusions: The expression of HER2 in CTC was associated with a longer DBFFS and the switching of HER2 expression between PIP and CTC may have impact on prognosis and treatment selection of BCBM.

The Prognostic Value of Brain Dysfunction in Critically Ill Patients with and without Sepsis: A Post Hoc Analysis of the ICON Audit

Brain dysfunction is associated with poor outcome in critically ill patients. In a post hoc analysis of the Intensive Care over Nations (ICON) database, we investigated the effect of brain dysfunction on hospital mortality in critically ill patients. Brain failure was defined as a neurological sequential organ failure assessment (nSOFA) score of 3–4, based on the assumed Glasgow Coma Scale (GCS) score. Multivariable analyses were performed to assess the independent roles of nSOFA and change in nSOFA from admission to day 3 (ΔnSOFA) for predicting hospital mortality. Data from 7192 (2096 septic and 5096 non-septic) patients were analyzed. Septic patients were more likely than non-septic patients to have brain failure on admission (434/2095 (21%) vs. 617/4665 (13%), p < 0.001) and during the ICU stay (625/2063 (30%) vs. 736/4665 (16%), p < 0.001). The presence of sepsis (RR 1.66 (1.31–2.09)), brain failure (RR 4.85 (3.33–7.07)), and both together (RR 5.61 (3.93–8.00)) were associated with an increased risk of in-hospital death, but nSOFA was not. In the 3280 (46%) patients in whom ΔnSOFA was available, sepsis (RR 2.42 (1.62–3.60)), brain function deterioration (RR 6.97 (3.71–13.08)), and the two together (RR 10.24 (5.93–17.67)) were associated with an increased risk of in-hospital death, whereas improvement in brain function was not.

Multi-Omics Analysis of Brain Metastasis Outcomes Following Craniotomy

BackgroundThe incidence of brain metastasis continues to increase as therapeutic strategies have improved for a number of solid tumors. The presence of brain metastasis is associated with worse prognosis but it is unclear if distinctive biomarkers can separate patients at risk for CNS related death.MethodsWe executed a single institution retrospective collection of brain metastasis from patients who were diagnosed with lung, breast, and other primary tumors. The brain metastatic samples were sent for RNA sequencing, proteomic and metabolomic analysis of brain metastasis. The primary outcome was distant brain failure after definitive therapies that included craniotomy resection and radiation to surgical bed. Novel prognostic subtypes were discovered using transcriptomic data and sparse non-negative matrix factorization.ResultsWe discovered two molecular subtypes showing statistically significant differential prognosis irrespective of tumor subtype. The median survival time of the good and the poor prognostic subtypes were 7.89 and 42.27 months, respectively. Further integrated characterization and analysis of these two distinctive prognostic subtypes using transcriptomic, proteomic, and metabolomic molecular profiles of patients identified key pathways and metabolites. The analysis suggested that immune microenvironment landscape as well as proliferation and migration signaling pathways may be responsible to the observed survival difference.ConclusionA multi-omics approach to characterization of brain metastasis provides an opportunity to identify clinically impactful biomarkers and associated prognostic subtypes and generate provocative integrative understanding of disease.

Acute heart and brain failure: a case report

Background Takotsubo syndrome (TTS) is characterized by often reversible but acute heart failure occurring after an emotional or physical trigger event. The ‘brain failure’ counterpart is posterior reversible encephalopathy syndrome (PRES) characterized by often reversible but acute neurological symptoms. This case report elaborates on a complex clinical scenario with co-existence of coronary artery disease, TTS and PRES and discusses the pathophysiology, differential diagnosis, and management. Case summary An 82-year-old woman presented with acute heart failure and generalized tonic-clonic seizures following an acute exacerbation of her chronic back pain. Brain magnetic resonance imaging demonstrated vasogenic oedema consistent with the diagnosis of PRES. Focal wall motion abnormalities on echocardiography without causal coronary stenoses on angiography were consistent with the diagnosis of TTS. After an interdisciplinary approach to differential diagnosis and treatment, the patient was discharged to geriatric rehabilitation without heart failure or neurological defects 4 weeks later. Discussion TTS and PRES share significant similarities in proposed pathogenesis, epidemiology, management, and clinical outcome. This case report highlights the need for early recognition of this rare association and multidisciplinary approach to diagnosis and treatment as both heart and brain disease may require early intervention up to rapid intensive care support.