Sigma 1 Receptor plays a prominent role in IL-24-induced cancer-specific apoptosis.

Interleukin-24 (IL-24), a member of the IL-10 cytokine family, is an immunomodulatory cytokine that also displays broad cancer-specific suppressor effects. The tumor suppressor activities of IL-24 include inhibition of angiogenesis, sensitization to chemotherapy, and cancer-specific apoptosis. We show that Sigma 1 Receptor (S1R), a ligand-regulated protein chaperone contributes to IL-24 induction of apoptosis. IL-24 generated from an adenovirus expressing IL-24 (Ad.IL-24) induces cancer-specific apoptosis by inducing an endoplasmic reticulum (ER) stress, reactive oxygen species production, and calcium mobilization. The present studies reveals that S1R is required for Ad.IL-24-induced cell death. We provide several lines of evidence to confirm a physical and functional interaction between IL-24 and S1R including: (a) S1R and IL-24 co-localize, as judged by immunocytochemical analysis studies; (b) S1R and IL-24 co-immunoprecipitate using either S1R or IL-24 antibody; (c) S1R agonist (+)-SKF10047 inhibits apoptosis by Ad.IL-24; (d) (+)-SKF10047-mediated inhibition of Ad.IL-24 results in: diminished ER stress protein expression; (e) Calcium mobilization; and (f) ROS production. Collectively, these data demonstrate that S1R interacts with IL-24 and suggest that IL-24:S1R interaction determines apoptosis induction by Ad.IL-24. These studies define Sigma 1 Receptor as a key initial mediator of IL-24 induction of cancer-specific killing. These findings have important implications for our understanding of IL-24 as a tumor suppressor protein as well as an immune modulating cytokine.

Anesthetic management and outcome in patients during endovascular therapy for acute stroke.

BACKGROUND: Studies of endovascular treatment for acute ischemic stroke have identified general anesthesia as a predictor for poor outcome in comparison with local anesthesia/sedation. This retrospective study attempts to identify modifiable factors associated with poor outcome, while adjusting for baseline stroke severity, in patients receiving general anesthesia. METHODS: We reviewed charts of 129 patients treated between January 2003 and September 2009. The primary outcome was the modified Rankin Score of 0-2 for 3 months poststroke. Predictors of neurologic outcome included baseline National Institutes of Health Stroke Scale score, blood glucose concentration, and age. Additional risk factors evaluated were prolonged stroke onset-treatment interval and systolic blood pressure less than 140 mmHg. Choice of local anesthesia or general anesthesia was recorded. RESULTS: The study group was 96 out of 129 patients for whom modified Rankin Scale scores were available; 48 patients received general anesthesia and 48 local anesthesia. The proportion of patients with "good" outcomes were 15% and 60% in the general anesthesia group and local anesthesia group, respectively (P < 0.001). Lowest systolic blood pressure and general anesthesia were correlated (r = -0.7, P < 0.001). Independent predictors for good neurologic outcome were local anesthesia, systolic blood pressure greater than 140 mmHg, and low baseline stroke scores. CONCLUSIONS: Adjusted for stroke severity, patients who received general anesthesia for treatment are less likely to have a good outcome than those managed with local anesthesia. This may be due to preintervention risk not included in the stroke severity measures. Hypotension, more frequent in the general anesthesia patients, may also contribute.

Continuation versus discontinuation of renin-angiotensin system inhibitors in patients admitted to hospital with COVID-19: a prospective, randomised, open-label trial.

BACKGROUND: Biological considerations suggest that renin-angiotensin system inhibitors might influence the severity of COVID-19. We aimed to evaluate whether continuing versus discontinuing renin-angiotensin system inhibitors (angiotensin-converting enzyme inhibitors or angiotensin receptor blockers) affects outcomes in patients admitted to hospital with COVID-19. METHODS: The REPLACE COVID trial was a prospective, randomised, open-label trial done at 20 large referral hospitals in seven countries worldwide. Eligible participants were aged 18 years and older who were admitted to hospital with COVID-19 and were receiving a renin-angiotensin system inhibitor before admission. Individuals with contraindications to continuation or discontinuation of renin-angiotensin system inhibitor therapy were excluded. Participants were randomly assigned (1:1) to continuation or discontinuation of their renin-angiotensin system inhibitor using permuted block randomisation, with allocation concealed using a secure web-based randomisation system. The primary outcome was a global rank score in which participants were ranked across four hierarchical tiers incorporating time to death, duration of mechanical ventilation, time on renal replacement or vasopressor therapy, and multiorgan dysfunction during the hospitalisation. Primary analyses were done in the intention-to-treat population. The REPLACE COVID trial is registered with ClinicalTrials.gov, NCT04338009. FINDINGS: Between March 31 and Aug 20, 2020, 152 participants were enrolled and randomly assigned to either continue or discontinue renin-angiotensin system inhibitor therapy (continuation group n=75; discontinuation group n=77). Mean age of participants was 62 years (SD 12), 68 (45%) were female, mean body-mass index was 33 kg/m2 (SD 8), and 79 (52%) had diabetes. Compared with discontinuation of renin-angiotensin system inhibitors, continuation had no effect on the global rank score (median rank 73 [IQR 40-110] for continuation vs 81 [38-117] for discontinuation; ß-coefficient 8 [95% CI -13 to 29]). There were 16 (21%) of 75 participants in the continuation arm versus 14 (18%) of 77 in the discontinuation arm who required intensive care unit admission or invasive mechanical ventilation, and 11 (15%) of 75 participants in the continuation group versus ten (13%) of 77 in the discontinuation group died. 29 (39%) participants in the continuation group and 28 (36%) participants in the discontinuation group had at least one adverse event (χ2 test of adverse events between treatment groups p=0·77). There was no difference in blood pressure, serum potassium, or creatinine during follow-up across the two groups. INTERPRETATION: Consistent with international society recommendations, renin-angiotensin system inhibitors can be safely continued in patients admitted to hospital with COVID-19. FUNDING: REPLACE COVID Investigators, REPLACE COVID Trial Social Fundraising Campaign, and FastGrants.

Evolutionary hypothesis for Chiari type I malformation.

Chiari I malformation (CM-I) is classically defined as a cerebellar tonsillar herniation (≥5 mm) through the foramen magnum. A decreased posterior fossa volume, mainly due to basioccipital hypoplasia and sometimes platybasia, leads to posterior fossa overcrowding and consequently cerebellar herniation. Regardless of radiological findings, embryological genetic hypothesis or any other postulations, the real cause behind this malformation is yet not well-elucidated and remains largely unknown. The aim of this paper is to approach CM-I under a broader and new perspective, conjoining anthropology, genetics and neurosurgery, with special focus on the substantial changes that have occurred in the posterior cranial base through human evolution. Important evolutionary allometric changes occurred during brain expansion and genetics studies of human evolution demonstrated an unexpected high rate of gene flow interchange and possibly interbreeding during this process. Based upon this review we hypothesize that CM-I may be the result of an evolutionary anthropological imprint, caused by evolving species populations that eventually met each other and mingled in the last 1.7 million years.

Spontaneous cervical artery dissection: an update on clinical and diagnostic aspects.

Spontaneous cervical arterial dissection (SCAD) is a non-traumatic tear or disruption in the wall of the internal carotid arteries or the vertebral arteries. It accounts for about 25% of strokes in patients aged under 45 years. Awareness of its clinical features and advances in imaging over the last two decades have contributed to earlier identification of this condition. SCAD has become the commonest form of vascular lesion identified in the cervical carotid and vertebral arteries, second only to atherosclerosis. This review is an update on the epidemiology, vulnerable arterial segments, risk factors, clinical features, diagnosis, current treatment and prognosis of SCAD.

Spontaneous cervical artery dissection: an update on clinical and diagnostic aspects / Dissecção espontânea da artéria cervical: atualização sobre aspectos clínicos e diagnósticos

Spontaneous cervical arterial dissection (SCAD) is a non-traumatic tear or disruption in the wall of the internal carotid arteries or the vertebral arteries. It accounts for about 25 percent of strokes in patients aged under 45 years. Awareness of its clinical features and advances in imaging over the last two decades have contributed to earlier identification of this condition. SCAD has become the commonest form of vascular lesion identified in the cervical carotid and vertebral arteries, second only to atherosclerosis. This review is an update on the epidemiology, vulnerable arterial segments, risk factors, clinical features, diagnosis, current treatment and prognosis of SCAD.

Dissecção arterial cervical espontânea (DACE) é uma laceração ou ruptura na parede de artérias cervicais responsáveis pela irrigação sanguínea cerebral: artérias carótidas internas e artérias vertebrais. É responsável por cerca de 25 por cento dos acidentes vasculares cerebrais isquêmicos em pacientes abaixo de 45 anos de idade. Ao longo das duas últimas décadas, com a maior conscientização sobre suas manifestações clínicas e o avanço das técnicas de neuroimagem, a DACE tem sido diagnosticada mais precocemente, tornando-se o tipo de lesão vascular mais comumente identificado nas artérias cervicais, sendo superada apenas pelas lesões ateroscleróticas. Esta revisão é uma atualização sobre a epidemiologia, segmentos arteriais mais vulneráveis, fatores de risco, manifestações clínicas, diagnóstico, tratamento e prognóstico da DACE.

Dissecção arterial cervical espontânea: aspectos clínicos e de imagem / Spontaneous cervical arterial dissection: clinical and imaging aspects

Foram estudados aspectos clínicos e de imagem da dissecção arterial espontânea em 36 pacientes com dissecção de artéria carótida interna (DACI) e 24 com dissecção de artéria vertebral (DAV). Aspectos clínicos e padrões de lesão arterial foram comparados entre os pacientes. Adicionalmente, avaliou-se a relação entre dissecção dolorosa e cefaléia primária (CP). Dores frontais, parietais e de qualidade pulsátil foram mais freqüentes na DACI, enquanto dores occipitais, nucais e de qualidade em facada, na DAV (p<0,05); O desempenho funcional foi melhor nos casos de DAV (p=0,047). Estenose foi mais freqüente na DAV (p=0,019), enquanto oclusão, na DACI (p=0,020). À presença de duplo lúmen foi mais freqüente na DACI (p=0,001), enquanto extravasamento de contraste, na DAV (p=0,032). Dissecção dolorosa não se associou a CP...

Clinical and imaging aspects of spontaneous arterial dissection were studied in 36 patients with internal carotid artery dissection (ICAD) and 24 with vertebral artery dissection (VAD). Clinical aspects and the patterns of arterial lesion were compared between patients with ICAD and VAD. Additionally, the relation between painful dissection and primary headache (PH) was evaluated. Pulsatile, frontal and parietal pains were more frequent in ICAD, whereas stabbing, occipital and nuchal pains were more frequent in VAD (p<0,05). Functional outcome was more frequent in VAD patients (p=0,047). Stenosis was more frequent in VAD (p=0,019), whereas occlusion, in ICAD (p=0,020). Double lumen sign was more frequent in ICAD (p=0,001), whereas extravasation of contrast medium was more frequent in VAD (p=0,032). Painful dissection was not related to the history of PH...