Neutrophil-to-Lymphocyte Ratio Predicts Early Neurological Deterioration after Endovascular Treatment in Patients with Ischemic Stroke

The worsening of neurological status that occurs early after acute ischemic stroke (AIS) remains a serious issue, and the inflammatory response plays a key role in stroke pathobiology. Recently, endovascular treatment (EVT) has revolutionized the management and outcome of patients with AIS due to either extracranial carotid disease or intracranial disease. The neutrophil-to-lymphocyte ratio (NLR) represents an easily available inflammatory biomarker. The aim of the study was to assess the relationship between the NLR at admission and the occurrence of early neurological deterioration (END) in patients with AIS who underwent EVT. Patients with AIS and proximal arterial occlusion in the anterior circulation undergoing EVT were retrospectively identified. Absolute neutrophil count (ANC) and absolute lymphocyte count (ALC) were collected from admission blood work to calculate the NLR. The study outcome was END defined as an increase in at least 4 points in NIHSS score or death between baseline and 24 h after the ischemic event. Patients included were 211, and END occurred in 30 (14.2%). Patients with older age (OR = 1.07, 95% CI: 1.02-1.13), higher serum glucose (OR = 1.01, 95% CI: 1.01-1.02), and higher NLR (OR = 1.011, 95% CI: 1.04-1.18) had an increased risk of END. The best predictive cut-off value of NLR was 6.4, and END occurred in 24.1% and 3.9% of the patients with NLR ≥ 6.4 and <6.4, respectively (p < 0.001). In patients with AIS undergoing EVT, higher NLR values predicted a higher risk of END. Biomarkers able to identify inflammatory mechanisms might identify novel treatment targets and enhance proof-of-concept trials of immunomodulation in stroke

Therapeutic Targeting of Acute Myeloid Leukemia by Gemtuzumab Ozogamicin

Simple Summary Gemtuzumab Ozogamicin (GO) is a drug approved for the treatment of acute myeloid leukemia (AML). It targets leukemic cells that express the CD33 molecule on their surface and brings the toxic agent calicheamicin inside the cell to kill it. Several studies have shown that AML patients can benefit of the addition of GO to chemotherapy during induction regimens, pre- and post-transplantation. Moreover, some disease features have been addressed or are under investigation for their capacity to predict response to GO, with the future aim of selecting AML patients that can mostly benefit of GO treatment. Acute myeloid leukemia (AML) is a complex hematological malignancy characterized by genetic and clinical heterogeneity and high mortality. Despite the recent introduction of novel pharmaceutical agents in hemato-oncology, few advancements have been made in AML for decades. In the last years, the therapeutic options have rapidly changed, with the approval of innovative compounds that provide new opportunities, together with new challenges for clinicians: among them, on 1 September, 2017 the Food and Drug Administration granted approval for Gemtuzumab Ozogamicin (GO) in combination with daunorubicin and cytarabine for the treatment of adult patients affected by newly diagnosed CD33(+) AML. Benefits of GO-based regimens were also reported in the pre- and post-transplantation settings. Moreover, several biomarkers of GO response have been suggested, including expression of CD33 and multidrug resistance genes, cytogenetic and molecular profiles, minimal residual disease and stemness signatures. Among them, elevated CD33 expression on blast cells and non-adverse cytogenetic or molecular risk represent largely validated predictors of good response

Impact of metabolic disorders on the structural, functional, and immunological integrity of the blood-brain barrier: Therapeutic avenues

: Mounting evidence has linked the metabolic disease to neurovascular disorders and cognitive decline. Using a murine model of a high-fat high-sugar diet mimicking obesity-induced type 2 diabetes mellitus (T2DM) in humans, we show that pro-inflammatory mediators and altered immune responses damage the blood-brain barrier (BBB) structure, triggering a proinflammatory metabolic phenotype. We find that disruption to tight junctions and basal lamina due to loss of control in the production of matrix metalloproteinases (MMPs) and their inhibitors (TIMPs) causes BBB impairment. Together the disruption to the structural and functional integrity of the BBB results in enhanced transmigration of leukocytes across the BBB that could contribute to an initiation of a neuroinflammatory response through activation of microglia. Using a humanized in vitro model of the BBB and T2DM patient post-mortem brains, we show the translatable applicability of our results. We find a leaky BBB phenotype in T2DM patients can be attributed to a loss of junctional proteins through changes in inflammatory mediators and MMP/TIMP levels, resulting in increased leukocyte extravasation into the brain parenchyma. We further investigated therapeutic avenues to reduce and restore the BBB damage caused by HFHS-feeding. Pharmacological treatment with recombinant annexin A1 (hrANXA1) or reversion from a high-fat high-sugar diet to a control chow diet (dietary intervention), attenuated T2DM development, reduced inflammation, and restored BBB integrity in the animals. Given the rising incidence of diabetes worldwide, understanding metabolic-disease-associated brain microvessel damage is vital and the proposed therapeutic avenues could help alleviate the burden of these diseases

The glucose transporter 2 regulates CD8⁺ T cell function via environment sensing

T cell activation is associated with a profound and rapid metabolic response to meet increased energy demands for cell division, differentiation and development of effector function. Glucose uptake and engagement of the glycolytic pathway are major checkpoints for this event. Here we show that the low-affinity, concentration-dependent glucose transporter 2 (Glut2) regulates the development of CD8+ T cell effector responses in mice by promoting glucose uptake, glycolysis and glucose storage. Expression of Glut2 is modulated by environmental factors including glucose and oxygen availability and extracellular acidification. Glut2 is highly expressed by circulating, recently primed T cells, allowing efficient glucose uptake and storage. In glucose-deprived inflammatory environments, Glut2 becomes downregulated, thus preventing passive loss of intracellular glucose. Mechanistically, Glut2 expression is regulated by a combination of molecular interactions involving hypoxia-inducible factor-1 alpha, galectin-9 and stomatin. Finally, we show that human T cells also rely on this glucose transporter, thus providing a potential target for therapeutic immunomodulation

A critical assessment of the current pharmacotherapy for the treatment of embolic strokes of undetermined source

Introduction: 'Embolic stroke of undetermined source' (ESUS) is a term coined to identify non-lacunar stroke whose mechanism is likely to be embolic, and the source remains unidentified. The best antithrombotic treatment for preventing stroke recurrence in this population has not been delineated. Areas covered: The authors summarize and critically appraise the currently available evidence about the antithrombotic treatment for preventing stroke recurrence in patients with ESUS. Randomized trials addressing this topic were identified through MEDLINE (accessed by PubMed, as of November 2021, week 4). Expert opinion: Recent randomized trials have failed to demonstrate a significant benefit of direct oral anticoagulants over aspirin in reducing the recurrence of cerebral infarctions in unselected cohorts of patients with ESUS. The heterogeneity and often overlap of embolic sources may be possible explanations for the overall absence of a benefit of oral anticoagulants in ESUS as a single homogeneous entity. The results of these trials and their subgroup analyses have provided important cues to understand the pathophysiology of ESUS. They have, furthermore, increased in the interest in researchers in identifying distinct etiological phenotypes within this stroke population. There is a good rationale for ongoing and future investigations in order to tailor antithrombotic treatment according to individual features of patients with ESUS

The EEG pen-on-paper sound: History and recent advances

: The electroencephalogram (EEG) is one of the most useful technologies for brain research and clinical neurology, characterized by non-invasiveness and high time resolution. The acquired traces are visibly displayed, but various studies investigate the translation of brain waves in sound (i.e., a process called sonification). Several articles have been published since 1934 about the sonification of EEG traces, in the attempt to identify the "brain-sound." However, for a long time this sonification technique was not used for clinical purposes. The analog EEG was in fact already equipped with an auditory output, although rarely mentioned in scientific papers: the pen-on-paper noise made by the writer unit. EEG technologists often relied on the sound that pens made on paper to facilitate the diagnosis. This article provides a sample of analog video-EEG recordings with audio support representing the strengths of a combined visual-and-auditory detection of different types of seizures. The purpose of the present article is to illustrate how the analog EEG "sounded," as well as to highlight the advantages of this pen-writing noise. It was considered so useful that early digital EEG devices could be equipped with special software to duplicate it digitally. Even in the present days, the sonification can be considered as an attempt to modify the EEG practice using auditory neurofeedback with applications in therapeutic interventions, cognitive improvement, and basic research

Liver fibrosis-4 score predicts outcome of patients with ischemic stroke undergoing intravenous thrombolysis

: Some evidence suggests a possible influence of liver disease on stroke prognosis. We investigated the association between fibrosis-4 (FIB-4) score, a marker of liver disease, and the 3-month outcome in patients with ischemic stroke undergoing intravenous thrombolysis. We also evaluated the rate of symptomatic intracranial hemorrhage after thrombolysis. In this prospective cohort study, we enrolled consecutive patients with ischemic stroke treated with thrombolysis who had a 3-month follow-up. The FIB-4 score was calculated and the validated cut-off values were used to indicate high/low risk of advanced liver fibrosis. The primary outcome was 3-month poor prognosis estimated as a modified Rankin scale score ≥3. Of the 264 included patients, 131 (49.62%) had a 3-month mRS ≥3, with a significantly higher FIB-4 score, compared to those with a mRS <3 score (adjp <0.001). When adjusted for possible confounders by multivariate logistic regression, FIB-4 score remained a significant predictor of poor outcome (OR 1.894, p = 0.011), along with history of atrial fibrillation (OR 3.488, p = 0.017), admission NIHSS score (OR 1.305, p < 0.001), and low values of hemoglobin (OR 0.730, p < 0.001). Mechanical thrombectomy had a favorable effect on patients' outcome (OR 0.201, p = 0.005). The risk of poor 3-month outcome was significantly higher among the 32 patients (12.1%) with high risk of severe fibrosis (p = 0.007). FIB-4 score values were also related to symptomatic intracranial hemorrhage (p = 0.004), specifically among patients with high probability of advanced hepatic fibrosis (p = 0.037). FIB-4 score can be considered as a promising independent predictor of poor prognosis in patients with acute ischemic stroke undergoing intravenous thrombolysis

Predictors of Pharmaco-Resistance in Patients with Post-Stroke Epilepsy

Objectives: The study aimed to explore the clinical predictors of pharmaco-resistance in patients with post-stroke epilepsy (PSE). Methods: Patients with epilepsy secondary to cerebral infarct or spontaneous intracerebral hemorrhage were included. The study outcome was the occurrence of pharmaco-resistance defined as the failure of adequate trials of two tolerated and appropriately chosen and used antiseizure medication schedules, whether as monotherapies or in combination, to achieve sustained seizure freedom. Results: One-hundred and fifty-nine patients with PSE and a median follow-up of 5 (3-9) years were included. The mean age of the patients at stroke onset was 56.7 (14.9) years, and 104 (65.4%) were males. In the study cohort, 29 participants were pharmaco-resistant. Age at stroke onset [odds ratio (OR) 0.97, 95% confidence interval (CI) 0.93-0.99; p = 0.044], history of intracerebral hemorrhage (OR 2.95, 95% CI 1.06-8.24; p = 0.039), severe stroke (OR 5.43, 95% CI 1.82-16.16; p = 0.002), status epilepticus as initial presentation of PSE (OR 7.90, 1.66-37.55; p = 0.009), and focal to bilateral tonic-clonic seizures (OR 3.19, 95% CI 1.16-8.79; p = 0.025) were independent predictors of treatment refractoriness. Conclusions: Pharmaco-resistance developed in approximately 20% of patients with PSE and was associated with younger age at stroke onset, stroke type and severity, status epilepticus occurrence, and seizure types

Autosomal recessive spino-cerebellar ataxia type 10 (SCAR10): clinical presentation associated with c.289delA ANO10 gene variant

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The latency of post-stroke epilepsy can predict drug resistance

Background and purpose: The progressive nature of epileptogenesis raises the question of whether the latent period may already carry information about the characteristics of the subsequent epilepsy. This study aimed to explore whether the time from stroke to epilepsy onset was related to the risk of drug resistance in patients with post-stroke epilepsy (PSE). Methods: Patients with epilepsy secondary to cerebral infarct or spontaneous intracerebral hemorrhage were included. Study outcome was the occurrence of drug resistance defined as failure of adequate trials of two tolerated and appropriately chosen and used antiseizure medication schedules to achieve sustained seizure freedom. Results: One-hundred and fifty-nine patients with PSE and a median follow-up of 5 [interquartile range (IQR) 3-9] years were included. In the study cohort, 29 (18.2%) participants were drug resistant. The median length of the time interval between stroke and PSE onset was 13 [IQR 7-15] months in drug resistant patients and 19 [IQR 14-42] months (p<0.001) in patients with seizure control. According to multivariable regression analysis, the time from stroke to PSE was an independent predictor of drug resistance (p<0.001). The risk of drug resistance was highest when the onset of PSE occurred within the first months from stroke and decreased progressively with a steeper decline over the first 12 months. Conclusions: Substantial variability may exist in the pathways leading to PSE and distinguish patients with a variable risk of drug resistance