The Protease-Activated Receptors (PARs) are G-protein-coupled receptors (GPCRs) characterized by a unique mechanism of activation. They carry built in their extended N-terminal structure their own ...activating agonist, in the form of a cryptic tethered ligand, unmasked by an irreversible proteolytic cleavage. Besides, PARs display several other particular properties, that converge and create interacting and intertwined layers of molecular processes regulating receptor's selective signaling with important biological and pharmacological consequences. These include the operation of multiple proteases, co-factors and protease inhibitors expressed in many types of cells and tissues, creating a dynamic balance between activators and inhibitors of PAR function in a tissue specific way. Membrane microdomain compartmentalization and allosteric modulation through intermolecular interactions between PARs adds further complexity to the receptor signaling and desensitization. Furthermore, molecular components interacting with thrombin and PARs take on new roles. In particular, activated protein C (APC) forms a significant negative feedback loop for thrombin with anticoagulant properties. In addition, APC exerts anti-inflammatory and direct neuroprotective effects in vivo and in vitro. This has informed the pharmacological dissection of anticoagulant from the anti-inflammatory and neuroprotective actions of APC and the generation of engineered APC mutations with diminished risk of serious bleeding, while preserving the cytoprotective effects of APC on cells. Even more important, these advances have made possible a paradigm shift, away from a "neurocentric" and towards a "vasculo-neuronal-inflammatory model of action", which supports novel pharmacological strategies targeting multiple disease mechanisms.
Objectives:
The cumulative safety and efficacy measures of percutaneous transluminal angioplasty and stenting (PTAS) for secondary stroke prevention in patients with symptomatic intracranial arterial ...stenosis (sICAS) have not previously been evaluated using a meta-analytical approach.
Methods:
We conducted a systematic review and random effects meta-analysis of all available randomized controlled trials (RCTs) evaluating the safety and efficacy of PTAS (in comparison with medical therapy) for sICAS.
Results:
Three RCTs (678 total patients) were included in the quantitative analysis. PTAS was associated with a higher risk of recurrent ischemic stroke in the territory of qualifying artery both within 30 days risk ratio (RR) = 2.21, 95% confidence interval (CI) 1.10–4.43 and 1 year (RR = 1.92, 95% CI 1.10–3.36). PTAS was also related to a higher risk of any ischemic stroke within 30 days from the index event (RR = 2.08, 95% CI 1.17–3.71). The risk for intracranial hemorrhage was found to be higher in PTAS patients both within 30 days (RR = 10.60, 95% CI 1.98–56.62) and 1 year (RR = 8.15, 95% CI 1.50–44.34). The composite outcome of any stroke or death within 1 year (RR = 2.29, 95% CI 1.13–4.66) and 2 years (RR = 1.52, 95% CI 1.04–2.21) was higher in PTAS than in medical therapy. PTAS was associated with a higher risk of any stroke or death within 2 years in the sICAS subgroup located in posterior circulation (RR = 2.37, 95% CI 1.27–4.42).
Conclusions:
PTAS is associated with adverse early and long-term outcomes and should not be recommended in patients with sICAS. Further research to identify subgroups of patients who could also serve as candidates for future interventional trials along with efforts to reduce procedure-related complications are needed.
Background:
Intravenous thrombolysis (IVT) remains the only approved systemic reperfusion treatment for acute ischemic stroke (AIS), however there are scarce data regarding outcomes and complications ...of IVT in Greece. We evaluated safety and efficacy outcomes of IVT for AIS in Greece using the Safe Implementation of Thrombolysis in Stroke: International Stroke Thrombolysis Register (SITS-ISTR) dataset.
Methods:
All AIS patients treated with IVT in Greece between December 2002 and July 2017 and recorded in the SITS-ISTR were evaluated. Demographics, risk factors, baseline stroke severity defined using National Institutes of Health Stroke Scale (NIHSS), and onset-to-treatment time (OTT) were recorded. Safety outcomes included symptomatic intracranial hemorrhage (sICH) and 3-month mortality rates. The efficacy outcomes evaluated a reduction in baseline NIHSS score at 2 and 24 h following IVT onset, 3-month favorable functional outcome FFO; modified Rankin scale (mRS) scores of 0–1 and 3-month functional independence (FI; mRS-scores of 0–2). The safety and efficacy outcomes were assessed comparatively with previously published data from SITS national and international registries.
Results:
A total of 523 AIS patients were treated with IVT in 12 Greek centers participating in the SITS-ISTR during the study period (mean age 62.4 ± 12.7; 34.6% women; median baseline NIHSS score: 11 points; median OTT: 150 min). The rates of sICH were 1.4%, 2.3%, and 3.8% according to the SIST-MOST, ECASS II, and NINDS criteria respectively. The median reduction in NIHSS score at 2 and 24 h was 3 interquartile range (IQR): 1–5 and 5 (IQR: 2–8) points respectively. The 3-month FI, FFO and mortality were 66.5%, 55.6% and 7.9%. All safety and efficacy outcomes were comparable with available data from SITS-ISTR in other European countries.
Conclusions:
Our study underscores the safety and efficacy of IVT for AIS in Greece. Additional action is necessary in order to increase the availability of IVT in the Greek population and to include more centers in the SITS-ISTR.
Chronic inflammation is a well-established background process in many age-related diseases. Many recent studies investigate the use of various inflammatory biomarkers such as C-reactive protein ...(CRP), interleukin-6, and interleukin-1 as predictors of physical and cognitive performance among elders. The phenotype of frailty has also been associated with underlying inflammatory mechanisms. The aim of this article was to review the literature referring to the correlation of CRP serum levels and frailty in older individuals. We tried to identify all relevant publications regarding the relation of CRP as an index of frailty in the elderly and its potential use. Although many studies in the recent medical literature positively associate serum CRP levels and frailty in older individuals, some do not, and some raise some interesting questions and set the basis for future studies. The association of CRP and frailty in elder patients should be considered when clinicians interpret inflammatory biomarkers in various clinical settings in such patients. Well-designed, prospective clinical trials are warranted to better assess the role and pathophysiology of frailty in the elderly and its mechanisms as also the exact role of CRP as an inflammatory marker and as a prognostic index in this syndrome.
A case of idiopathic basal ganglia calcification in a 56-year-old woman with parkinsonism and cognitive impairment is described. The nigrostriatal dopaminergic pathway and regional cerebral blood ...flow were evaluated using dopamine transporter (DAT) brain single photon emission tomography combined with a low-dose x-ray computerized tomography transmission (hybrid SPECT/CT) and Tc-99m HMPAO brain perfusion SPECT study, respectively.DAT SPECT/CT imaging revealed a reduction in DAT binding in both striatum regions coinciding with bilateral calcifications in the basal ganglia. Brain perfusion scan showed hypoperfusion in basal ganglia regions, posterior parietal cortex bilaterally, left frontopolar and dorsolateral prefrontal cortex, and left temporal lobe. These findings correlated well with the clinical condition of the patient.Mineralization may play a critical role in the pathogenesis of neuronal degeneration. Cortical perfusion changes in patients may better explain the patientʼs altered cognitive and motor functions.
Abstract The etiology of recurrent stroke is probably multifactorial and many recurrences remain unexplained by conventional risk factors. The purpose of this study is to investigate if common ...carotid artery intima-media thickness (CCA-IMT), an established vascular risk factor, can predict recurrence in first-ever stroke survivors. Two hundred and eighty-four consecutive patients with a first-ever ischemic stroke were investigated with carotid ultrasonography and were screened for the first recurrent stroke up to 12 months. Sixteen (5.6%, 95% CI: 3.5–9.0%) recurrent ischemic strokes were recorded. Among demographic data, conventional vascular risk factors, presenting stroke features and ultrasonographic measurements, CCA-IMT was the only parameter that differed significantly between those who suffered a recurrent stroke and those who did not. Cox’s regression analysis adjusted for confounding factors, showed that CCA-IMT was the only independent predictor of stroke recurrence (HR 1.65; 95% CI: 1.11–2.46%). We propose that CCA-IMT measurements may help to identify stroke patients at higher risk for recurrence and to plan secondary prevention strategies.
Objective
Patent foramen ovale (PFO) can be detected in up to 43% of patients with cryptogenic cerebral ischemia undergoing investigation with transesophageal echocardiography (TEE). The diagnostic ...value of transthoracic echocardiography (TTE) in the detection of PFO in patients with cryptogenic ischemic stroke or transient ischemic attack has not been compared with that of transcranial Doppler (TCD) using a comprehensive meta‐analytical approach.
Methods
We performed a systematic literature review to identify all prospective observational studies of patients with cryptogenic cerebral ischemia that provided both sensitivity and specificity measures of TTE, TCD, or both compared to the gold standard of TEE.
Results
Our literature search identified 35 eligible studies including 3,067 patients. The pooled sensitivity and specificity for TCD was 96.1% (95% confidence interval CI = 93.0–97.8%) and 92.4% (95% CI = 85.5–96.1%), whereas the respective measures for TTE were 45.1% (95% CI = 30.8–60.3%) and 99.6% (95% CI = 96.5–99.9%). TTE was superior in terms of higher positive likelihood ratio values (LR+ = 106.61, 95% CI = 15.09–753.30 for TTE vs LR+ = 12.62, 95% CI = 6.52–24.43 for TCD; p = 0.043), whereas TCD demonstrated lower negative likelihood values (LR− = 0.04, 95% CI = 0.02–0.08) compared to TTE (LR− = 0.55, 95% CI = 0.42–0.72; p < 0.001). Finally, the area under the summary receiver operating curve (AUC) was significantly greater (p < 0.001) in TCD (AUC = 0.98, 95% CI = 0.97–0.99) compared to TTE studies (AUC = 0.86, 95% CI = 0.82–0.89).
Interpretation
TCD is more sensitive but less specific compared to TTE for the detection of PFO in patients with cryptogenic cerebral ischemia. The overall diagnostic yield of TCD appears to outweigh that of TTE. Ann Neurol 2016;79:625–635
Functional single-nucleotide polymorphisms (SNPs) of inflammatory cytokines have been previously related to the occurrence of an ischemic stroke (IS). We investigated whether five functional SNPs ...(i.e., TNF-α-308G>A, IL6-174G>C, IL12B 1188A>C, IL4-589C>T, and IL10-1082G>A) might be associated with the age of onset and 6-month outcome of an acute IS. A probe-free real-time PCR methodology was used to genotype 145 consecutively admitted cases with a first-ever IS. Simple Kaplan-Mayer and adjusted Cox regression analyses showed no association between inflammatory genotypes and the age of IS onset. IL6-174G>C, IL12B 1188A>C, IL4-589C>T, and IL10-1082G>A were not found to significantly contribute to the long-term outcome of the disease. However, carriage of the TNF-α-308 GG genotype was significantly associated with reduced odds for an adverse outcome. Larger studies are needed to confirm our results.
We compared the efficacy, duration, safety, length of hospital stay of a frameless fiducial-less brain biopsy with those of the standard frame-based stereotactic biopsy.
This prospective cohort study ...enrolled 56 adult patients: (1) for whom no conclusive diagnosis could be reached noninvasively; (2a) who had lesions involving deep-seated and eloquent areas, multifocal lesions, or lesions for which craniotomy and lesion removal was not indicated, or (2b) were poor candidates for craniotomy (> 80 years of age and/or with serious comorbidities). Frameless and frame-based biopsy were performed in 28 patients each RESULTS: A diagnosis was not made in four cases (14.3%) of the frame-based biopsy group and in three cases (10.7%) of the frameless biopsy group, in spite of accurate targeting (
= 1.0). The mean duration of the whole procedure (preparatory steps outside the operating room OR, inside the OR, surgery) was 111.3 minutes for the frame-based biopsy and 79.1 minutes for the frameless biopsy (
= 0.001). No statistically significant differences between the two methods were found concerning new neurologic symptoms, new abnormal findings in postoperative computed tomography (CT) and length of postoperative hospital stay (LOS). The smallest diameter of a successfully biopsied lesion was 15 mm for both groups.
The frameless fiducial-less brain biopsy was equally efficacious and safe compared with the standard stereotactic frame-based biopsy. The overall duration of frameless biopsy is shorter than that of frame-based biopsy, mainly because the preparatory steps in frameless biopsy require less time. However, the overall time spent in the OR did not differ between the two groups. The LOS also did not differ significantly.
Childhood primary angiitis of the central nervous system (cPACNS) is an increasingly recognized inflammatory brain disease in children.
We present a case of a 17-year-old boy with recurrent ischemic ...events over a short time period. Diagnosis of angiography positive cPACNS was made based on neuroimaging findings while secondary causes or mimics of CNS vasculitis were meticulously excluded. The patient exhibited rapid deterioration of his condition with poor initial response to immunosuppressive treatment.
Recognition of cPACNS remains a challenge because of rarity of disease, unexplained etiopathogenesis, protean clinical presentation, as well as lack of specific laboratory and neuroimaging markers.
•Childhood primary angiitis of the central nervous system (cPACNS) is an increasingly recognized inflammatory brain disease in children.•Diagnosis of cPACNS relies on confirmatory MRI and angiographic findings, while excluding an underlying systemic condition.•Our case highlights the complexities in diagnosis and management of cPACNS in the actual clinical setting.
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