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1.
Isr Med Assoc J ; 25(12): 853-854, 2022 Dec 01.
Artículo en Inglés | MEDLINE | ID: mdl-37584409

RESUMEN

Endovascularly retrieved clots may be a potential resource for diagnosing stroke etiology. This method may influence secondary prevention treatment. We measure thrombin activity eluted by serially washing clots. We concluded that an assay measuring the change in thrombin in clots retrieved during acute stroke endovascular thrombectomy procedures may serve as a diagnostic marker of the origin of the clot. The suggested mechanism for these differences may be the clot location before its retrieval, with high blood flow causing thrombin washout in atherosclerotic clots, in contrast to atrium appendage low blood flow retaining high thrombin levels.


Asunto(s)
Fibrilación Atrial , Accidente Cerebrovascular Isquémico , Accidente Cerebrovascular , Trombosis , Humanos , Trombina , Fibrilación Atrial/diagnóstico , Fibrilación Atrial/complicaciones , Trombosis/etiología , Accidente Cerebrovascular/diagnóstico , Accidente Cerebrovascular/etiología , Accidente Cerebrovascular Isquémico/complicaciones
2.
J Neurosci Res ; 99(3): 966-976, 2021 03.
Artículo en Inglés | MEDLINE | ID: mdl-33296953

RESUMEN

Many coagulation factor proteases are increased in the brain during ischemic stroke. One of these proteases is plasmin. In this study we established a novel method for direct quantitative measurement of plasmin activity in male mouse brain slices using a sensitive fluorescent substrate in the presence of specific protease inhibitors. In both the ischemic and contralateral hemispheres, plasmin activity increased 3, 6, and 24 hr following stroke in comparison to healthy mice (F(3, 72) = 39.5, p < 0.0001, repeated measures ANOVA) after the induction of permanent middle cerebral artery occlusion (PMCAo). Plasmin activity was higher in the ischemic hemisphere (F(1,36) = 9.1, p = 0.005) and there was a significant interaction between time and ischemic hemisphere (F(3,36) = 4.4, p = 0.009). Plasmin activity was correlated with infarct volume (R2  = 0.5289, p = 0.0009 by Spearman). The specificity of the assay was verified utilizing tissue-type plasminogen activator (tPA)-deficient mice which, as expected, had significantly lower levels of plasmin 24 hr following ischemia compared to wild-type mice (ischemic (0.6 ± 0.23 and 1.94 ± 0.5, respectively), p = 0.049 and contralateral hemispheres (0.13 ± 0.14 and 0.75 ± 0.10, respectively), p = 0.018 by t test). There is a time-dependent increase in plasmin levels and an association of higher levels of plasmin with larger infarct volumes in an experimental stroke model. This suggests caution in the use of recombinant tPA (rtPA) and that plasmin inhibition in the brain may be a therapeutic target in acute ischemic stroke.


Asunto(s)
Pruebas de Enzimas/métodos , Fibrinolisina/metabolismo , Accidente Cerebrovascular Isquémico/enzimología , Animales , Encéfalo/metabolismo , Encéfalo/patología , Infarto Encefálico/patología , Infarto de la Arteria Cerebral Media , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Modelos Animales , Activador de Tejido Plasminógeno/deficiencia
3.
Neuroepidemiology ; 55(5): 354-360, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-34237727

RESUMEN

INTRODUCTION: The COVID-19 pandemic overwhelmed health-care systems worldwide, and medical care for other acute diseases was negatively impacted. We aimed to investigate the effect of the COVID-19 outbreak on admission rates and in-hospital care for acute stroke and transient ischemic attack (TIA) in Israel, shortly after the start of the pandemic. METHODS: We conducted a retrospective observational study, based on data reported to the Israeli National Stroke Registry from 7 tertiary hospitals. All hospital admissions for acute stroke or TIA that occurred between January 1 and April 30, 2020 were included. Data were stratified into 2 periods according to the timing of COVID-19 restrictions as follows: (1) "pre-pandemic" - January 1 to March 7, 2020 and (2) "pandemic" - March 8 to April 30, 2020. We compared the weekly counts of hospitalizations between the 2 periods. We further investigated changes in demographic characteristics and in some key parameters of stroke care, including the percentage of reperfusion therapies performed, time from hospital arrival to brain imaging and to thrombolysis, length of hospital stay, and in-hospital mortality. RESULTS: 2,260 cases were included: 1,469 in the pre-COVID-19 period and 791 in the COVID-19 period. Hospital admissions significantly declined between the 2 periods, by 48% for TIA (rate ratio [RR] = 0.52; 95% CI 0.43-0.64) and by 29% for stroke (RR = 0.71; 95% CI 0.64-0.78). No significant changes were detected in demographic characteristics and in most parameters of stroke management. While the percentage of reperfusion therapies performed remained unchanged, the absolute number of patients treated with reperfusion therapies seemed to decrease. Higher in-hospital mortality was observed only for hemorrhagic stroke. CONCLUSION: The marked decrease in admissions for acute stroke and TIA, occurring at a time of a relatively low burden of COVID-19, is of great concern. Public awareness campaigns are needed as patients reluctant to seek urgent stroke care are deprived of lifesaving procedures and secondary prevention treatments.


Asunto(s)
COVID-19 , Hospitalización/estadística & datos numéricos , Accidente Cerebrovascular/terapia , Anciano , Anciano de 80 o más Años , Femenino , Humanos , Masculino , Persona de Mediana Edad , Pandemias , Sistema de Registros , Estudios Retrospectivos
4.
Lupus ; 30(5): 775-784, 2021 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-33554716

RESUMEN

INTRODUCTION: Antiphospholipid syndrome (APS) is an autoimmune disorder manifested by thromboembolic events, recurrent spontaneous abortions and elevated titers of circulating antiphospholipid antibodies. In addition, the presence of antiphospholipid antibodies seems to confer a fivefold higher risk for stroke or transient ischemic attack. Although the major antigen of APS is ß2 glycoprotein I, it is now well established that antiphospholipid antibodies are heterogeneous and bind to various targets. Recently, antibodies to Annexin A2 (ANXA2) have been reported in APS. This is of special interest since data indicated ANXA2 as a key player in fibrinolysis. Therefore, in the present study we assessed whether anti-ANXA2 antibodies play a pathological role in thrombosis associated disease. MATERIALS AND METHODS: Mice were induced to produce anti-ANXA2 antibodies by immunization with ANXA2 (iANXA2) and control mice were immunized with adjuvant only. A middle cerebral artery occlusion stroke model was applied to the mice. The outcome of stroke severity was assessed and compared between the two groups. RESULTS: Our results indicate that antibodies to ANXA2 lead to a more severe stroke as demonstrated by a significant larger stroke infarct volume (iANXA2 133.9 ± 3.3 mm3 and control 113.7 ± 7.4 mm3; p = 0.017) and a more severe neurological outcome (iANXA2 2.2 ± 0.2, and control 1.5 ± 0.18; p = 0.03). CONCLUSIONS: This study supports the hypothesis that auto-antibodies to ANXA2 are an independent risk factor for cerebral thrombosis. Consequently, we propose screening for anti-ANXA2 antibodies should be more widely used and patients that exhibit the manifestations of APS should be closely monitored by physicians.


Asunto(s)
Anexina A2/inmunología , Síndrome Antifosfolípido/inmunología , Autoanticuerpos/inmunología , Trombosis Intracraneal/metabolismo , Adulto , Animales , Anexina A2/administración & dosificación , Anexina A2/metabolismo , Anticuerpos Antifosfolípidos/sangre , Síndrome Antifosfolípido/complicaciones , Síndrome Antifosfolípido/metabolismo , Autoanticuerpos/metabolismo , Autoinmunidad/inmunología , Modelos Animales de Enfermedad , Femenino , Fibrinólisis/inmunología , Humanos , Infarto de la Arteria Cerebral Media/inmunología , Infarto de la Arteria Cerebral Media/fisiopatología , Inyecciones Subcutáneas , Trombosis Intracraneal/etiología , Ataque Isquémico Transitorio/inmunología , Ratones , Ratones Endogámicos BALB C/inmunología , Persona de Mediana Edad , Factores de Riesgo , Índice de Severidad de la Enfermedad , Accidente Cerebrovascular/inmunología , beta 2 Glicoproteína I/metabolismo
5.
Cardiology ; 146(3): 375-383, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-33582661

RESUMEN

BACKGROUND: Percutaneous device closure was shown to effectively prevent recurrent strokes in patients with patent foramen ovale (PFO). Whether this protective effect is relevant for patients with hypercoagulable states (HCSs) is unknown as they were not represented in prior studies. METHODS: Data on 136 consecutive patients with a PFO and clinically significant HCS were retrospectively collected. PFO closure and antithrombotic regimen were decided on an individual basis by the treating physicians, and adherence to therapy was routinely evaluated. The outcome was the occurrence of cerebrovascular accident (CVA) or transient ischemic attack (TIA). RESULTS: HCS types consisted of antiphospholipid syndrome (31%), factor-5 Leiden mutation (22%), prothrombin mutation (18%), protein S deficiency (15%), protein C deficiency (7%), methyl-tetra-hydro folate reductase mutation (5%), and essential thrombocytosis (2%). 102 patients (75%) were maintained on anticoagulants and the remaining on antiplatelet therapy. PFO closure was undertaken in 85 (63%); antithrombotic therapy was not interrupted prior to or after the procedures. At a mean follow-up of 46 ± 8 months, 23 patients (17%; 95% confidence interval, 9.3-22%) experienced an outcome event, mainly in the form of CVAs (n = 15, 65%). In multivariable analysis, PFO closure was associated with a 5-fold decrease in the risk of CVA/TIA (p = 0.02). This effect was independent of the type of HCS or antithrombotic therapy. CONCLUSIONS: Among patients with HCSs maintained on anticoagulant or antiplatelet therapies, PFO closure was associated with a significantly lower risk of CVA or TIA.


Asunto(s)
Foramen Oval Permeable , Ataque Isquémico Transitorio , Accidente Cerebrovascular , Cateterismo Cardíaco , Fibrinolíticos/uso terapéutico , Foramen Oval Permeable/complicaciones , Foramen Oval Permeable/cirugía , Humanos , Ataque Isquémico Transitorio/prevención & control , Recurrencia , Estudios Retrospectivos , Accidente Cerebrovascular/tratamiento farmacológico , Accidente Cerebrovascular/etiología , Accidente Cerebrovascular/prevención & control , Resultado del Tratamiento
6.
Stroke ; 48(4): 1092-1094, 2017 04.
Artículo en Inglés | MEDLINE | ID: mdl-28258255

RESUMEN

BACKGROUND AND PURPOSE: Despite overwhelming evidence for the benefits of anticoagulation in patients with brain ischemia and atrial fibrillation, vast underuse has been reported. METHODS: Use of anticoagulation for secondary stroke prevention was assessed in the National Acute Stroke Israeli Survey registry (NASIS) of hospitalized patients with atrial fibrillation and acute brain ischemia. Logistic regression analysis was performed to evaluate the effects of clinical covariates on anticoagulation therapy at discharge, and anticoagulation use over time was assessed in subgroups of patients with identified barriers to anticoagulation utilization. RESULTS: There were 1254 survivors of acute brain ischemia with atrial fibrillation (mean age 77.2±10.6 years; 57.7% female). Between 2004 and 2013, the proportion of patients discharged on anticoagulation increased from 55% to 76.2%, and among those without perceived contraindications from 70% to 96% (P<0.0001). Older age, greater stroke severity, earlier registry period, and presence of contraindications were independent predictors of withholding therapy. Increased anticoagulation use over the years was observed even in patients with barriers to anticoagulation use, including patients with potential contraindications (P<0.001). CONCLUSIONS: In survivors of acute brain ischemia with atrial fibrillation, we observed a substantial increase in anticoagulation utilization within less than a decade. This change was mainly driven by greater utilization of anticoagulation in subgroups with traditional clinical barriers to anticoagulation use, indicating a shift in physicians' perceptions of the risk-benefit ratio of anticoagulation.


Asunto(s)
Anticoagulantes/uso terapéutico , Fibrilación Atrial/tratamiento farmacológico , Isquemia Encefálica/tratamiento farmacológico , Sistema de Registros/estadística & datos numéricos , Medición de Riesgo , Accidente Cerebrovascular/tratamiento farmacológico , Factores de Edad , Anciano , Anciano de 80 o más Años , Anticoagulantes/efectos adversos , Femenino , Humanos , Israel , Masculino , Persona de Mediana Edad , Prevención Secundaria , Índice de Severidad de la Enfermedad
7.
Isr Med Assoc J ; 19(9): 553-556, 2017 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-28971638

RESUMEN

BACKGROUND: Computed tomography (CT) brain perfusion is a relatively new imaging method that can be used to differentiate patients following epileptic seizures in the setting of acute neurological deficits (e.g., hemiparesis, hemiplegia, hemianopsia, aphasia) who arrive at the emergency room with a suspected stroke. OBJECTIVES: To evaluate brain perfusion changes in patients who had an epileptic seizure. METHODS: We retrospectively identified 721 patients who presented at our stroke center between 2012 and 2015 with a suspected acute stroke and underwent examination thorough a stroke protocol, including cerebral CT perfusion (CTP) and CT angiography (CTA) within 8 hours from the onset of symptoms. RESULTS: Out of 721 patients, 25 presented with ictal electroencephalography (EEG) findings within 24-72 hours from symptom onset without evidence of vascular occlusion on CTA. While 15 patients had to be excluded from the study due to concomitant brain pathology, we found a specific reduction in cerebral blood volume and cerebral blood flow occurring at the ictal zone, which was identified by a post hoc EEG investigation. CONCLUSIONS: Our study shows that CTP is an easily accessible tool in emergency department setting for the detection of changes in blood flow dynamics among postictal patients. Thus, we propose the use of CTP in emergency settings to discriminate between postictal changes and acute vascular events.


Asunto(s)
Encéfalo/irrigación sanguínea , Encéfalo/diagnóstico por imagen , Angiografía Cerebral/métodos , Circulación Cerebrovascular , Angiografía por Tomografía Computarizada/métodos , Epilepsia/diagnóstico por imagen , Accidente Cerebrovascular/diagnóstico por imagen , Diagnóstico Diferencial , Electroencefalografía , Humanos , Estudios Retrospectivos , Factores de Tiempo
9.
Front Neurol ; 15: 1404099, 2024.
Artículo en Inglés | MEDLINE | ID: mdl-38817547

RESUMEN

Background: Information regarding the safety and efficacy of specific direct oral anticoagulants (DOAC) in the treatment of cerebral sinus and venous thrombosis (CSVT) is scarce. Apixaban is one of the most frequently prescribed DOACs. Therefore, we aimed to compare the safety and efficacy of Apixaban with those of vitamin k antagonists (VKA) in patients with CSVT. Methods: Prospective CSVT databases from seven academic medical centers were retrospectively analyzed. Patients treated with Apixaban were compared to those treated with VKA. Data on demographics, clinical presentations, risk factors, radiological and outcome parameters were studied. Results: Overall, 403 patients were included in the analysis. Of them, 48 (12%) were treated with Apixaban, and 355 (88%) were treated with VKA. Rates of coagulopathies were significantly higher in the VKA-treated patients but no other differences between the groups were found in baseline characteristics and underlying etiology. No significant differences were found between groups in efficacy or safety parameters including the rates of recanalization, favorable outcomes, one-year mortality, seizures, intracranial hemorrhage or CSVT recurrences. Conclusion: Our data suggests that Apixaban may be safe and effective for patients with CSVT. These results should be tested in prospective randomized clinical studies.

10.
J Neurointerv Surg ; 15(8): 771-775, 2023 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-35853698

RESUMEN

BACKGROUND: Vessel tortuosity poses a challenge during endovascular treatment of neurovascular lesions. Bendit Technologies (Petah Tikva, Israel) has developed flexible, steerable microcatheters designed with unique bending and torquing capabilities. OBJECTIVE: To describe our first-in-human trial of Bendit21. METHODS: Bendit21 was used in our exploratory, prospective, multicenter, open-label, single-arm clinical study, and in two compassionate use cases. Procedures were conducted at four centers in Austria, Germany, Israel, and the United States between May 2021 and March 2022, in patients with neurovascular conditions. The primary endpoints were device-related safety events, successful navigation through the neurovasculature, and, when intended, successful delivery of contrast or therapy. RESULTS: Two patients with giant aneurysms were treated successfully under compassionate use approval. The clinical study included 25 patients (mean age: 63.4±11.8 years; 32.0% female). Fourteen patients (56.0%) had aneurysms, two had arteriovenous malformations/fistulas (8.0%), one had a stroke (4.0%), four (16.0%) had intracranial stenosis, and four (16.0%) had other conditions. Bendit21 was used without a guidewire in 12/25 (48.0%) procedures. Bendit21 was successfully navigated through the vasculature without delays or spasms in all cases (100%). Contrast was delivered as intended in 7/7 (100%) cases. Therapeutic devices were delivered successfully with Bendit as intended in 14/18 (77.8%) cases; four deficiencies occurred in three patients with aneurysms, in whom delivery of coils, an intrasaccular device, or a flow diverter was attempted. There were no device-related safety events or mortalities. CONCLUSIONS: Our initial clinical experience with the Bendit21 microcatheter demonstrates its usefulness in achieving technical success in patients with challenging neurovascular conditions.


Asunto(s)
Fístula Arteriovenosa , Embolización Terapéutica , Procedimientos Endovasculares , Aneurisma Intracraneal , Humanos , Femenino , Persona de Mediana Edad , Anciano , Masculino , Estudios Prospectivos , Aneurisma Intracraneal/diagnóstico por imagen , Aneurisma Intracraneal/terapia , Cateterismo , Embolización Terapéutica/métodos , Procedimientos Endovasculares/métodos , Fístula Arteriovenosa/terapia , Resultado del Tratamiento , Stents
11.
CNS Drugs ; 37(12): 1111-1121, 2023 12.
Artículo en Inglés | MEDLINE | ID: mdl-37991705

RESUMEN

BACKGROUND: Levetiracetam is widely used in post-stroke epilepsy. However, it is suspected to possess P-glycoprotein (P-gp) induction properties, and therefore, a potentially significant interaction with direct oral anticoagulants (DOACs). We aimed to search for ischemic stroke signals with levetiracetam and the DOACs. METHODS: In this retrospective pharmacovigilance study, we used the FAERS database to identify ischemic stroke events associated with DOACs and concomitant use of levetiracetam. We evaluated disproportionate reporting by the adjusted reporting odds ratio (adjROR) and the lower bound of the shrinkage 95% confidence interval. When shrinkage is positive, an increased risk of a specific adverse event occurrence is emphasized over the sum of the individual risks when these same drugs are used separately. RESULTS: We identified 1841 (1.5%), 3731 (5.3%), 338 (4.9%), and 1723 (1.3%) ischemic stroke reports with apixaban, dabigatran, edoxaban, and rivaroxaban, respectively. The adjROR of the interaction effect was 3.57 (95% CI 2.81-4.58) between DOACs and levetiracetam. The shrinkage analysis detected an interaction between each of the DOACs and levetiracetam. The logistic model and shrinkage analysis failed to detect an interaction when queried for hemorrhagic stroke. A significant signal in the classical enzyme inducer, carbamazepine, strengthened our results (adjROR; 8.47, 95% CI 5.37-13.36). CONCLUSIONS: Our study shows a strong signal for the levetiracetam interaction with the DOACs. Our findings suggest implementation of a drug monitoring strategy.


Asunto(s)
Fibrilación Atrial , Accidente Cerebrovascular Isquémico , Humanos , Anticoagulantes/efectos adversos , Levetiracetam/efectos adversos , Estudios Retrospectivos , Farmacovigilancia , Fibrilación Atrial/tratamiento farmacológico , Piridonas/efectos adversos , Accidente Cerebrovascular Isquémico/tratamiento farmacológico , Administración Oral
12.
J Am Heart Assoc ; 12(14): e029635, 2023 07 18.
Artículo en Inglés | MEDLINE | ID: mdl-37421277

RESUMEN

Background Cancer is associated with an increased risk of acute ischemic stroke, including large vessel occlusions. Whether cancer status affects outcomes in patients with large vessel occlusions that undergo endovascular thrombectomy remains unknown. Methods and Results All consecutive patients undergoing endovascular thrombectomy for large vessel occlusions were recruited into a prospective ongoing multicenter database, and the data were retrospectively analyzed. Patients with active cancer were compared with patients with cancer in remission. Association of cancer status with 90-day functional outcome and mortality were calculated in multivariable analyses. We identified 154 patients with cancer and large vessel occlusions that underwent endovascular thrombectomy (mean age, 74±11; 43% men; median National Institutes of Health Stroke Scale 15). Of the included patients, 70 (46%) had a remote history of cancer or cancer in remission, and 84 (54%) had active disease. Outcome data at 90 days poststroke were available for 138 patients (90%) and was classified as favorable in 53 (38%). Patients with active cancer were younger and more often smoked but did not significantly differ from those without malignancy in other risk factors, stroke severity, stroke subtype, or procedural variables. Favorable outcome rates among patients with active cancer did not significantly differ compared with those seen in patients without active cancer, but mortality rates were significantly higher among patients with active cancer on univariate and multivariable analyses. Conclusions Our study suggests that endovascular thrombectomy is safe and efficacious in patients with history of malignancy as well as in those with active cancer at the time of stroke onset, although mortality rates are higher among patients with active cancer.


Asunto(s)
Arteriopatías Oclusivas , Isquemia Encefálica , Procedimientos Endovasculares , Accidente Cerebrovascular Isquémico , Neoplasias , Accidente Cerebrovascular , Lesiones del Sistema Vascular , Masculino , Humanos , Persona de Mediana Edad , Anciano , Anciano de 80 o más Años , Femenino , Isquemia Encefálica/etiología , Accidente Cerebrovascular Isquémico/etiología , Accidente Cerebrovascular Isquémico/complicaciones , Estudios Retrospectivos , Estudios Prospectivos , Resultado del Tratamiento , Accidente Cerebrovascular/etiología , Accidente Cerebrovascular/complicaciones , Trombectomía/efectos adversos , Trombectomía/métodos , Lesiones del Sistema Vascular/etiología , Neoplasias/complicaciones , Neoplasias/epidemiología , Procedimientos Endovasculares/efectos adversos , Procedimientos Endovasculares/métodos
13.
Int J Emerg Med ; 16(1): 50, 2023 Aug 11.
Artículo en Inglés | MEDLINE | ID: mdl-37568103

RESUMEN

BACKGROUND: To assess the effect of a commercial artificial intelligence (AI) solution implementation in the emergency department on clinical outcomes in a single level 1 trauma center. METHODS: A retrospective cohort study for two time periods-pre-AI (1.1.2017-1.1.2018) and post-AI (1.1.2019-1.1.2020)-in a level 1 trauma center was performed. The ICH algorithm was applied to 587 consecutive patients with a confirmed diagnosis of ICH on head CT upon admission to the emergency department. Study variables included demographics, patient outcomes, and imaging data. Participants admitted to the emergency department during the same time periods for other acute diagnoses (ischemic stroke (IS) and myocardial infarction (MI)) served as control groups. Primary outcomes were 30- and 120-day all-cause mortality. The secondary outcome was morbidity based on Modified Rankin Scale for Neurologic Disability (mRS) at discharge. RESULTS: Five hundred eighty-seven participants (289 pre-AI-age 71 ± 1, 169 men; 298 post-AI-age 69 ± 1, 187 men) with ICH were eligible for the analyzed period. Demographics, comorbidities, Emergency Severity Score, type of ICH, and length of stay were not significantly different between the two time periods. The 30- and 120-day all-cause mortality were significantly reduced in the post-AI group when compared to the pre-AI group (27.7% vs 17.5%; p = 0.004 and 31.8% vs 21.7%; p = 0.017, respectively). Modified Rankin Scale (mRS) at discharge was significantly reduced post-AI implementation (3.2 vs 2.8; p = 0.044). CONCLUSION: The added value of this study emphasizes the introduction of artificial intelligence (AI) computer-aided triage and prioritization software in an emergent care setting that demonstrated a significant reduction in a 30- and 120-day all-cause mortality and morbidity for patients diagnosed with intracranial hemorrhage (ICH). Along with mortality rates, the AI software was associated with a significant reduction in the Modified Ranking Scale (mRs).

14.
Elife ; 112022 09 20.
Artículo en Inglés | MEDLINE | ID: mdl-36125261

RESUMEN

T cells use kinetic proofreading to discriminate antigens by converting small changes in antigen-binding lifetime into large differences in cell activation, but where in the signaling cascade this computation is performed is unknown. Previously, we developed a light-gated immune receptor to probe the role of ligand kinetics in T cell antigen signaling. We found significant kinetic proofreading at the level of the signaling lipid diacylglycerol (DAG) but lacked the ability to determine where the multiple signaling steps required for kinetic discrimination originate in the upstream signaling cascade (Tiseher and Weiner, 2019). Here, we uncover where kinetic proofreading is executed by adapting our optogenetic system for robust activation of early signaling events. We find the strength of kinetic proofreading progressively increases from Zap70 recruitment to LAT clustering to downstream DAG generation. Leveraging the ability of our system to rapidly disengage ligand binding, we also measure slower reset rates for downstream signaling events. These data suggest a distributed kinetic proofreading mechanism, with proofreading steps both at the receptor and at slower resetting downstream signaling complexes that could help balance antigen sensitivity and discrimination.


Asunto(s)
Antígenos , Diglicéridos , Antígenos/metabolismo , Cinética , Ligandos , Receptores de Antígenos de Linfocitos T/metabolismo , Linfocitos T
15.
Front Neurol ; 13: 783795, 2022.
Artículo en Inglés | MEDLINE | ID: mdl-35493844

RESUMEN

Background: Cerebral sinus venous thrombosis (CSVT) is a rare neurovascular entity, usually associated with acquired or genetic hypercoagulable states. In up to 30% of the cases it remains idiopathic. Bone marrow proliferation disorders that are associated with Janus Kinase 2 V617F mutation (JAK-2) are known causes of the systemic and cerebral thrombosis-at times despite normal blood counts-for which hematologic treatment exists. However, JAK-2 prevalence in the CSVT cases is not clear. Methods: In this retrospective analysis, data of 236 patients with CSVT admitted to two tertiary centers between 2010 and 2020 were analyzed, with emphasis on laboratory and imaging data and clinical and interventional outcomes. Results: A total of 236 patients were included in the analysis. The patients' median age was 42 years and the average age was 44 years (±19 years), with 59% female patients. JAK-2 positivity rate was 18% (among 77 patients tested for the mutation). Patients with normal blood counts on presentation comprised 36% of the JAK-2 positive cases. Other hypercoagulability states were also investigated, with the antiphospholipid syndrome (APLA) showing the highest prevalence (11%) followed by other etiologies including oral contraceptive use, Factor V Leiden, prothrombin mutation, and malignancy. Selected JAK-2, APLA, and prothrombin mutation cases showed a more severe clinical course. Conclusion: JAK-2 mutation is underdiagnosed and its screening may be warranted in the cases of idiopathic CSVT, even despite normal blood counts, to allow disease-modifying treatment and blood cell count monitoring. JAK-2, APLA, and prothrombin mutation may be associated with a more complicated clinical course.

16.
Cerebrovasc Dis ; 31(3): 271-7, 2011.
Artículo en Inglés | MEDLINE | ID: mdl-21178352

RESUMEN

BACKGROUND: Chronic kidney disease (CKD) is associated with both a risk of adverse vascular outcome and a risk of bleeding. We have tested the hypothesis that in the setting of an acute intracerebral hemorrhage (ICH), CKD is associated with poor outcome and with larger hematoma volume. METHODS: We examined the association between CKD and ICH characteristics and outcome within a prospective cohort study of consecutive patients hospitalized with an acute stroke and followed for 1 year. CKD was categorized by the estimated baseline glomerular filtration rate into moderate/severe impairment (<45), mild impairment (45-60) and no impairment (>60 ml/min/1.73 m(2)). RESULTS: Among 128 patients with an ICH (mean age = 71.7 ± 12.3 years, 41.4% women) 46.1% had CKD (23.4% mild and 22.7% moderate/severe). Patients with moderate/severe impairment had >4-fold adjusted hazard ratio for mortality over 1 year (4.29; 95% CI = 1.69-10.90) compared to patients with no impairment. The hematoma volumes [median (25-75%)] were 15.3 ml (5.4-37.5) in patients with no impairment, 16.6 (6.8-36.9) in mild impairment and 50.2 (10.4-109.1) in moderate/severe impairment (p = 0.009). The location of the hematoma was lobar in 12% with no impairment, 17% with mild impairment and 39% with moderate/severe impairment (p = 0.02). Patients with moderate/severe impairment exhibited a 2.3-fold higher hematoma volume (p = 0.04) and a >6-fold higher odds of lobar location (95% CI = 1.59-24.02) as compared to no impairment. Further adjustment for antiplatelet use and for presence of leukoaraiosis attenuated the association with hematoma volume (p = 0.15), while moderate/severe impairment was associated with an adjusted OR of 5.35 (95% CI = 1.18-24.14) for lobar location. CONCLUSIONS: Presence of moderate/severe CKD among patients with ICH is associated with larger, lobar hematomas and with poor outcome.


Asunto(s)
Hemorragia Cerebral/complicaciones , Hematoma/etiología , Enfermedades Renales/complicaciones , Anciano , Anciano de 80 o más Años , Hemorragia Cerebral/diagnóstico por imagen , Hemorragia Cerebral/mortalidad , Distribución de Chi-Cuadrado , Enfermedad Crónica , Femenino , Tasa de Filtración Glomerular , Hematoma/diagnóstico por imagen , Hematoma/mortalidad , Humanos , Israel , Estimación de Kaplan-Meier , Riñón/fisiopatología , Enfermedades Renales/mortalidad , Enfermedades Renales/fisiopatología , Modelos Logísticos , Estudios Longitudinales , Masculino , Persona de Mediana Edad , Oportunidad Relativa , Pronóstico , Modelos de Riesgos Proporcionales , Estudios Prospectivos , Sistema de Registros , Medición de Riesgo , Factores de Riesgo , Índice de Severidad de la Enfermedad , Factores de Tiempo , Tomografía Computarizada por Rayos X
18.
World Neurosurg ; 147: e354-e362, 2021 03.
Artículo en Inglés | MEDLINE | ID: mdl-33346051

RESUMEN

BACKGROUND: Spinal dural arteriovenous fistulas (SDAVFs) are rare vascular malformations. Digital subtraction angiography is the modality of choice to demonstrate the malformation before endovascular embolization or open surgical repair. Angiographically occult SDAVFs have been previously reported. Surgical considerations in SDAVFs with misleading angiography findings have not yet been assessed. METHODS: A retrospective evaluation of charts and imaging files of patients operated on for SDAVF in 2018-2019 at a single institution was performed. All patients were referred to surgery following failure of endovascular embolization or owing to clinical and radiographic deterioration in the presence of an angiographically occult lesion. Cases were comprehensively reviewed and evaluated for surgical considerations in these lesions. RESULTS: This case series included 4 cases. Two patients underwent embolization before surgical repair but continued to deteriorate neurologically, and 2 patients had a failed embolization attempt owing to a torturous vascular network. In all 4 patients, exploration was successful, yielding either improvement or stabilization of neurological status. Indocyanine green injection for microscopically integrated fluorescent angiography contributed to the identification of the supplying vessels and confirmed the SDAVF closure. CONCLUSIONS: SDAVFs should be treated promptly after diagnosis. In cases with high suspicion for SDAVF with occult or misleading angiography findings, spinal exploration should be pursued with no delay. Indocyanine green-assisted microscopic angiography may contribute to exploratory spine surgery for SDAVF closure.


Asunto(s)
Malformaciones Vasculares del Sistema Nervioso Central/cirugía , Médula Espinal/cirugía , Columna Vertebral/cirugía , Insuficiencia del Tratamiento , Anciano , Angiografía de Substracción Digital/métodos , Embolización Terapéutica/métodos , Procedimientos Endovasculares/métodos , Femenino , Humanos , Masculino , Persona de Mediana Edad
19.
Intern Emerg Med ; 16(8): 2261-2268, 2021 11.
Artículo en Inglés | MEDLINE | ID: mdl-33650082

RESUMEN

The emergence of Covid-19 has caused a pandemic and is a major public health concern. Covid-19 has fundamentally challenged the global health care system in all aspects. However, there is a growing concern for the subsequent detrimental effects of continuing delays or adjustments on time-dependent treatments for Covid-19 negative patients. Patients arriving to the ED with STEMIs and acute CVA are currently presumed to have delays due to Covid-19 related concerns. The objective of this paper is to evaluate the implications of the Covid-19 pandemic on non-Covid19 patients in emergency care settings. We conducted a retrospective study from February 2020 to April 2020 and compared this to a parallel period in 2019 to assess the impact of the Covid-19 pandemic on three distinct non-Covid-19 ED diagnosis that require immediate intervention. Our primary outcome measures were time to primary PCI in acute STEMI, time to fibrinolysis in acute CVA, and time to femoral hip fracture correction surgery. Our secondary outcome measure included a composite outcome of length of stay in hospital and mortality. From 1 February 2020 to 30 April 2020, the total referrals to ED diagnosed with STEMI, Hip fracture and CVA of which required intervention were 197 within Covid-19 group 2020 compared to 250 in the control group 2019. Mean duration to intervention (PCI, surgery and tPA, respectively) did not differ between COVID-19 group and 2019 group. Among femoral hip fracture patients', the referral numbers to ED were significantly lower in Covid-19 era (p = 0.040) and the hospitalization stay was significantly shorter (p = 0.003). Among CVA patients', we found statistical differences among the number of referrals and the patients' age. Coping with the Covid-19 pandemic presents a challenge for the general healthcare system. Our results suggest that with proper management, despite the obstacles of isolation policies and social distancing, any negative impact on the quality of health care for the non-Covid-19 patients can be minimized in the emergency department setting.


Asunto(s)
COVID-19/epidemiología , Servicios Médicos de Urgencia/tendencias , Servicio de Urgencia en Hospital/tendencias , Accesibilidad a los Servicios de Salud/tendencias , Tiempo de Tratamiento/tendencias , Diagnóstico Tardío/tendencias , Humanos , Estudios Retrospectivos
20.
J Neurol Sci ; 423: 117357, 2021 04 15.
Artículo en Inglés | MEDLINE | ID: mdl-33725592

RESUMEN

BACKGROUND: According to the latest reported data from the National Acute Stroke Israeli Survey (NASIS), around 18,000 strokes occur annually in Israel. Data regarding disparities in stroke care between the Jewish and the Arab populations in Israel are lacking. AIMS: We wished to compare demographics, comorbidities, stroke characteristics and outcomes between Jewish and Arab stroke patients in Israel that were acutely treated with intravenous thrombolysis (IVT) and/or endovascular thrombectomy (EVT), in order to test if there are disparities or any ethnic-specific parameters. METHODS: The National Acute Stroke Israeli registry of patients undergoing revascularization (NASIS-REVASC) prospectively enrolled patients in six comprehensive stroke centers between 1/2014 and 3/2016. In this observational research, we compared demographics, comorbidities, time metrics, stroke characteristics and outcomes between Jewish and Arab patients enrolled. RESULTS: NASIS-REVASC included 1432 patients out of which 143 (10%) were of Arab ethnicity and 1289 (90%) of Jewish ethnicity. Arab patients were significantly younger (66 ± 14 vs. 73 ± 29, p = 0·004), exhibited higher rates of smoking and diabetes (31% vs. 18% and 57% vs. 34%, p < 0·001 for both), and were less often treated with systemic thrombolysis (48% vs. 59%, p = 0·012). However, the rates of any interventional treatment with either intravenous thrombolysis or endovascular thrombectomy as well as the rates of favorable outcomes and mortality were comparable between groups. CONCLUSIONS: Despite several baseline differences between Arab and Jewish Israeli stroke patients, treatment allocations, survival and functional outcomes were similar indicating lack of disparity in stroke care among patients treated acutely with IVT and/or EVT in Israel. DATA ACCESS STATEMENT: Full data is available following a formal request to the NASIS-REVASC registry at the Israeli Health Ministry.


Asunto(s)
Judíos , Accidente Cerebrovascular , Árabes , Humanos , Israel/epidemiología , Sistema de Registros , Accidente Cerebrovascular/epidemiología , Accidente Cerebrovascular/terapia
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