scholarly journals Cytokine-Laden Extracellular Vesicles Predict Patient Prognosis after Cerebrovascular Accident

2021 ◽  
Vol 22 (15) ◽  
pp. 7847
Author(s):  
Anthony Fringuello ◽  
Philip D. Tatman ◽  
Tadeusz Wroblewski ◽  
John A. Thompson ◽  
Xiaoli Yu ◽  
...  
Keyword(s):  
Extracellular Vesicles ◽  
Inflammatory Cytokines ◽  
Hemorrhagic Stroke ◽  
Term Outcome ◽  
Long Term Outcome ◽  
Interleukin 7 ◽  
Poor Outcomes ◽  
Patient Prognosis ◽  
The Brain

Background: A major contributor to disability after hemorrhagic stroke is secondary brain damage induced by the inflammatory response. Following stroke, global increases in numerous cytokines—many associated with worse outcomes—occur within the brain, cerebrospinal fluid, and peripheral blood. Extracellular vesicles (EVs) may traffic inflammatory cytokines from damaged tissue within the brain, as well as peripheral sources, across the blood–brain barrier, and they may be a critical component of post-stroke neuroinflammatory signaling. Methods: We performed a comprehensive analysis of cytokine concentrations bound to plasma EV surfaces and/or sequestered within the vesicles themselves. These concentrations were correlated to patient acute neurological condition by the Glasgow Coma Scale (GCS) and to chronic, long-term outcome via the Glasgow Outcome Scale-Extended (GOS-E). Results: Pro-inflammatory cytokines detected from plasma EVs were correlated to worse outcomes in hemorrhagic stroke patients. Anti-inflammatory cytokines detected within EVs were still correlated to poor outcomes despite their putative neuroprotective properties. Inflammatory cytokines macrophage-derived chemokine (MDC/CCL2), colony stimulating factor 1 (CSF1), interleukin 7 (IL7), and monokine induced by gamma interferon (MIG/CXCL9) were significantly correlated to both negative GCS and GOS-E when bound to plasma EV membranes. Conclusions: These findings correlate plasma-derived EV cytokine content with detrimental outcomes after stroke, highlighting the potential for EVs to provide cytokines with a means of long-range delivery of inflammatory signals that perpetuate neuroinflammation after stroke, thus hindering recovery.

Molecular targets of lithium action

2003 ◽  
Vol 15 (6) ◽  
pp. 316-340 ◽  
Author(s):  
B Corbella ◽  
E Vieta
Keyword(s):  
Bipolar Disorder ◽  
Molecular Mechanisms ◽  
Molecular Targets ◽  
Mood Stabilizers ◽  
Lithium Cation ◽  
Therapeutic Effects ◽  
Term Outcome ◽  
Long Term Outcome ◽  
The Brain

Lithium is an effective drug for both the treatment and prophylaxis of bipolar disorder. However, the precise mechanism of lithium action is not yet well understood. Extensive research aiming to elucidate the molecular mechanisms underlying the therapeutic effects of lithium has revealed several possible targets. The behavioral and physiological manifestations of the illness are complex and are mediated by a network of interconnected neurotransmitter pathways. Thus, lithium's ability to modulate the release of serotonin at presynaptic sites and modulate receptor-mediated supersensitivity in the brain remains a relevant line of investigation. However, it is at the molecular level that some of the most exciting advances in the understanding of the long-term therapeutic action of lithium will continue in the coming years. The lithium cation possesses the selective ability, at clinically relevant concentrations, to alter the PI second-messenger system, potentially altering the activity and dynamic regulation of receptors that are coupled to this intracellular response. Subtypes of muscarinic receptors in the limbic system may represent particularly sensitive targets in this regard. Likewise, preclinical data have shown that lithium regulates arachidonic acid and the protein kinase C signaling cascades. It also indirectly regulates a number of factors involved in cell survival pathways, including cAMP response element binding protein, brain-derived neurotrophic factor, bcl-2 and mitogen-activated protein kinases, and may thus bring about delayed long-term beneficial effects via under-appreciated neurotrophic effects. Identification of the molecular targets for lithium in the brain could lead to the elucidation of the pathophysiology of bipolar disorder and the discovery of a new generation of mood stabilizers, which in turn may lead to improvements in the long-term outcome of this devastating illness (1).

scholarly journals Senescent stromal cells promote cancer resistance through SIRT1 loss-potentiated overproduction of small extracellular vesicles

2020 ◽  
Author(s):  
Liu Han ◽  
Qilai Long ◽  
Shenjun Li ◽  
Qixia Xu ◽  
Boyi Zhang ◽  
...  
Keyword(s):  
Drug Resistance ◽  
Cancer Cells ◽  
Extracellular Vesicles ◽  
Stromal Cells ◽  
Cancer Resistance ◽  
Term Outcome ◽  
Long Term Outcome ◽  
Age Related ◽  
Lysosomal Acidification

ABSTRACTCellular senescence is a potent tumor-suppressive program that prevents neoplastic events. Paradoxically, senescent cells develop an inflammatory secretome, termed the senescence-associated secretory phenotype (SASP) and implicated in age-related pathologies including cancer. Here we report that senescent cells actively synthesize and release small extracellular vesicles (sEVs) with a distinctive size distribution. Mechanistically, SIRT1 loss supports accelerated sEV production despite enhanced proteome-wide ubiquitination, a process correlated with ATP6V1A downregulation and defective lysosomal acidification. Once released, senescent stromal sEVs significantly alter the expression profile of recipient cancer cells and enhance their aggressiveness, specifically drug resistance mediated by expression of ATP binding cassette subfamily B member 4 (ABCB4). Targeting SIRT1 with an agonist SRT2104 prevents development of cancer resistance through restraining sEV production by senescent stromal cells. In clinical oncology, sEVs in peripheral blood of posttreatment cancer patients are readily detectable by routine biotechniques, presenting a novel biomarker to monitor therapeutic efficacy and to predict long term outcome. Together, our study identifies a distinct mechanism supporting pathological activities of senescent cells, and provides a novel avenue to circumvent advanced human malignancies by co-targeting cancer cells and their surrounding microenvironment, which contributes to drug resistance via secretion of sEVs from senescent stromal cells.

The Unforgettable Encephalitis

2018 ◽  
pp. 133-138
Author(s):  
Aaron E. Miller ◽  
Tracy M. DeAngelis ◽  
Michelle Fabian ◽  
Ilana Katz Sand
Keyword(s):  
Immunosuppressive Agents ◽  
Autoimmune Encephalitis ◽  
Hippocampal Damage ◽  
Term Outcome ◽  
Long Term Outcome ◽  
Hyperintense Signal ◽  
Laboratory Investigations ◽  
Mesial Temporal Lobe ◽  
The Brain

Leucine-rich glioma-inactivated 1 (LGI1) limbic encephalitis is an autoimmune encephalitis characterized by subacute cognitive impairment, amnesia, seizures, faciobrachial dystonic seizures (FBDS), and hyponatremia. MRI of the brain typically demonstrates abnormal T2/FLAIR hyperintense signal in the mesial temporal lobe, hippocampal regions. CSF is surprisingly bland, and laboratory investigations often disclose a hyponatremia. Patients with LGI1 encephalitis generally respond to immunotherapies such as glucocorticoids, intravenous immunoglobulin (IVIg), and plasma exchange and steroid-sparing immunosuppressive agents. The etiology of LGI1 encephalitis can be either autoimmune or paraneoplastic, more commonly the former. Reported prognosis is favorable in about two-thirds of cases; however, some patients can relapse, and long-term outcome can be poor if diagnosis is delayed and residual memory impairment from hippocampal damage occurs.

scholarly journals Sodium sulfide prevents water diffusion abnormality in the brain and improves long term outcome after cardiac arrest in mice

Resuscitation ◽  
2012 ◽  
Vol 83 (10) ◽  
pp. 1292-1297 ◽  
Author(s):  
Kotaro Kida ◽  
Shizuka Minamishima ◽  
Huifang Wang ◽  
JiaQian Ren ◽  
Kazim Yigitkanli ◽  
...  
Keyword(s):  
Cardiac Arrest ◽  
Sodium Sulfide ◽  
Water Diffusion ◽  
Term Outcome ◽  
Long Term Outcome ◽  
The Brain

scholarly journals Effect of Adherence to Antihypertensive Medication on the Long-Term Outcome After Hemorrhagic Stroke in Korea

Hypertension ◽  
2018 ◽  
Vol 72 (2) ◽  
pp. 391-398 ◽  
Author(s):  
Jinkwon Kim ◽  
Cheryl D. Bushnell ◽  
Hye Sun Lee ◽  
Sang Won Han
Keyword(s):  
Antihypertensive Medication ◽  
Hemorrhagic Stroke ◽  
Term Outcome ◽  
Long Term Outcome

scholarly journals Brain Biomarkers of Long-term Outcome of Neonatal Onset Urea Cycle Disorder

2016 ◽  
Author(s):  
Maha Mourad ◽  
Johannes Häberle ◽  
Matthew Whitehead ◽  
Tamar Stricker ◽  
Andrea L. Gropman
Keyword(s):  
Urea Cycle ◽  
Ammonia Level ◽  
Long Term Effects ◽  
Inborn Errors ◽  
Term Outcome ◽  
Long Term Outcome ◽  
Plasma Ammonia ◽  
Neonatal Onset ◽  
The Brain

Urea cycle disorders (UCDs) are common inborn errors of metabolism, with an incidence of one in 30,000 births. They are caused by deficiencies in any of six enzymes and two carrier proteins, the most common being Ornithine Transcarbamylase Deficiency (OTCD). OTCD results in impairment to excrete nitrogen, causing toxic buildup of ammonia with resultant encephalopathy. Hyperammonemia (HA) induces the conversion of glutamate to glutamine in the brain. Excess glutamine in the brain causes osmotic changes cerebral edema, changes in astrocyte morphology, and cell death. Acute symptoms of HA include vomiting, hyperventilation, seizures, and irritability. Long-term neurological changes include deficits in working memory and executive function. To date, there are no predictors of prognosis of infants with neonatal onset OTCD outside of plasma ammonia level at presentation and duration of hyperammonemic coma. We provide a comprehensive analysis of a 16-year-old male with neonatal onset of OTCD as an example of how brain biomarkers may be useful to monitor disease course and outcome. This male presented at 8 days post natal with plasma ammonia and glutamine of 677 and 4024 micromol/L and had a missense mutation in Exon 4 (p.R129H). Treatment included protein restriction, sodium benzoate, and citrulline, arginine, and iron. He suffered recurrent acute hyperammonemic episodes despite compliance, triggered by infections or catabolic stressors. We discuss the long-term effects of the hyperammonemic episodes by following MRI based disease biomarkers.

scholarly journals How to Explain Multidrug Resistance in Epilepsy?

2005 ◽  
Vol 5 (3) ◽  
pp. 107-112 ◽  
Author(s):  
Wolfgang Löscher
Keyword(s):  
Drug Targets ◽  
Initial Response ◽  
Efflux Transporters ◽  
Drug Efflux ◽  
Term Outcome ◽  
Long Term Outcome ◽  
Causative Mechanism ◽  
The Brain ◽  
Antiepileptic Drug Therapy

Despite advancements in antiepileptic therapy, about one third of people with epilepsy will remain intractable to medication. The initial response to antiepileptic drug therapy is highly predictive of long-term outcome. However, the mechanisms of medical intractability of epilepsy are only incompletely understood. Current interest is focused on two hypotheses: overexpression of drug efflux transporters and alterations in drug targets in the brain, with the most relevant causative mechanism(s) still to be elucidated.

Medical Management of Hemorrhagic Stroke

2018 ◽  
pp. 221-238
Author(s):  
Shashank Shekhar ◽  
Shreyas Gangadhara ◽  
Rebecca Sugg
Keyword(s):  
Early Diagnosis ◽  
Diagnostic Imaging ◽  
Medical Management ◽  
Hemorrhagic Stroke ◽  
Altered Mental Status ◽  
Acute Onset ◽  
Term Outcome ◽  
Long Term Outcome ◽  
Clinical Presentations

Since the management of hemorrhagic stroke differs from that of ischemic stroke, prompt, accurate, and early diagnosis is vital in the management of patients who present with acute onset of focal neurologic symptoms and/or with altered mental status. Diagnostic imaging in the form of computed tomography scan or magnetic resonance imaging and a vessel study is required to ascertain the bleeding characteristic, location, and etiology. A multidisciplinary approach is required in the management of hemorrhagic stroke. Early diagnosis and treatment of the hemorrhagic stroke impacts the long-term outcome of such patients. This chapter reviews the common clinical presentations, diagnostic imaging modalities and prehospital and emergency department medical management of the most common types of hemorrhagic stroke.

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