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BACKGROUND: The optimal treatment for acute minor ischemic stroke is still undefined. and options include dual antiplatelet treatment (DAPT), intravenous thrombolysis (IVT), or their combination. We aimed to investigate benefits and risks of combining IVT and DAPT versus DAPT alone in patients with MIS. METHODS AND RESULTS: This is a prespecified propensity score-matched analysis from a prospective multicentric real-world study (READAPT [Real-Life Study on Short-Term Dual Antiplatelet Treatment in Patients With Ischemic Stroke or Transient Ischemic Attack]). We included patients with MIS (National Institutes of Health Stroke Scale score at admission ≤5), without prestroke disability (modified Rankin scale [mRS] score ≤2). The primary outcomes were 90-day mRS score of 0 to 2 and ordinal mRS distribution. The secondary outcomes included 90-day risk of stroke and other vascular events and 24-hour early neurological improvement or deterioration (≥2-point National Institutes of Health Stroke Scale score decrease or increase from the baseline, respectively). From 1373 patients with MIS, 240 patients treated with IVT plus DAPT were matched with 427 patients treated with DAPT alone. At 90 days, IVT plus DAPT versus DAPT alone showed similar frequency of mRS 0 to 2 (risk difference, 2.3% [95% CI -2.0% to 6.7%]; P=0.295; risk ratio, 1.03 [95% CI 0.98-1.08]; P=0.312) but more favorable ordinal mRS scores distribution (odds ratio, 0.57 [95% CI 0.41-0.79]; P<0.001). Compared with patients treated with DAPT alone, those combining IVT and DAPT had higher 24-hour early neurological improvement (risk difference, 20.9% [95% CI 13.1%-28.6%]; risk ratio, 1.59 [95% CI 1.34-1.89]; both P<0.001) and lower 90-day risk of stroke and other vascular events (hazard ratio, 0.27 [95% CI 0.08-0.90]; P=0.034). There were no differences in safety outcomes. CONCLUSIONS: According to findings from this observational study, patients with MIS may benefit in terms of better functional outcome and lower risk of recurrent events from combining IVT and DAPT versus DAPT alone without safety concerns. REGISTRATION: URL: https://www.clinicaltrials.gov; Unique identifier: NCT05476081.
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BACKGROUND AND PURPOSE: Randomized controlled trials (RCTs) proved the efficacy of short-term dual antiplatelet therapy (DAPT) in secondary prevention of minor ischemic stroke or high-risk transient ischemic attack (TIA). We aimed at evaluating effectiveness and safety of short-term DAPT in real-world, where treatment use is broader than in RCTs. METHODS: READAPT (REAl-life study on short-term Dual Antiplatelet treatment in Patients with ischemic stroke or Transient ischemic attack) (NCT05476081) was an observational multicenter real-world study with a 90-day follow-up. We included patients aged 18+ receiving short-term DAPT soon after ischemic stroke or TIA. No stringent NIHSS and ABCD2 score cut-offs were applied but adherence to guidelines was recommended. Primary effectiveness outcome was stroke (ischemic or hemorrhagic) or death due to vascular causes, primary safety outcome was moderate-to-severe bleeding. Secondary outcomes were the type of ischemic and hemorrhagic events, disability, cause of death, and compliance to treatment. RESULTS: We included 1920 patients; 69.9% started DAPT after an ischemic stroke; only 8.9% strictly followed entry criteria or procedures of RCTs. Primary effectiveness outcome occurred in 3.9% and primary safety outcome in 0.6% of cases. In total, 3.3% cerebrovascular ischemic recurrences occurred, 0.2% intracerebral hemorrhages, and 2.7% bleedings; 0.2% of patients died due to vascular causes. Patients with NIHSS score ⩽5 and those without acute lesions at neuroimaging had significantly higher primary effectiveness outcomes than their counterparts. Additionally, DAPT start >24 h after symptom onset was associated with a lower likelihood of bleeding. CONCLUSIONS: In real-world, most of the patients who receive DAPT after an ischemic stroke or a TIA do not follow RCTs entry criteria and procedures. Nevertheless, short-term DAPT remains effective and safe in this population. No safety concerns are raised in patients with low-risk TIA, more severe stroke, and delayed treatment start.
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Postsynthetic diversification of peptides through selective modification of endogenous amino acid side chains has enabled significant advances in peptide drug discovery while expanding the biological and medical chemistry space. However, current tools have been focused on the modification of reactive polar and ionizable side chains, whereas the decoration of aromatic systems (e.g., the N(in) of the tryptophan) has been a long-standing challenge. Here, we introduce metallaphotocatalysis in solid-phase peptide synthesis for the on-resin orthogonal N-arylation of relevant tryptophan-containing peptides. The protocol allows the chemoselective introduction of a new C(sp2)-N bond at the N(in) of tryptophan in biologically active protected peptide sequences in the presence of native redox-sensitive side chains. The fusion of metallaphotocatalysis with solid-phase peptide synthesis opens new perspectives in diversifying native amino acid side chains.
Subject(s)
Peptides , Tryptophan , Tryptophan/chemistry , Peptides/chemistry , Amino Acids/chemistry , Oxidation-Reduction , Solid-Phase Synthesis TechniquesABSTRACT
INTRODUCTION: To evaluate the access to treatments with intravenous thrombolysis (IVT) and/or mechanical thrombectomy (MT) in acute ischemic stroke patients admitted to stroke units (SUs) of Veneto region (Italy) according to current "hub-and-spoke" model from 2017 to 2021. PATIENTS AND METHODS: We retrospectively analyzed data on treatments with IVT and/or MT for stroke patients admitted to the 23 SUs (6 Hubs and 17 Spokes) of the 6 macro-areas including 9 local sanitary units (LSUs) and 2 hospitals. RESULTS: We reported 6093 treatments with IVT alone, 1114 with IVT plus MT, and 921 with MT alone. Number of stroke unit (SU) beds/100,000 inhabitants ranges from 2.3 to 2.8, and no difference was found among different macro-areas. Number of treatments/100,000 inhabitants/year ranges from 19 to 34 for IVT alone, from 2 to 7 for IVT plus MT, and from 2 to 5 for MT alone. Number of IVT alone/SU bed/year ranges from 9 to 21 in the Hub and from 6 to 12 in the Spokes. Rate of IVT plus MT in patients directly arrived in the same LSU's Hub ranges from 50 to 81%, likewise the one of MT alone ranges from 49 to 84%. CONCLUSIONS: Treatment target rates of IVT and MT set by Action Plan for Stroke in Europe 2018-2030 has been globally exceeded in the Veneto region. However, the target rate of MT and access revascularization treatments is heterogeneous among different macro-areas. Further efforts should be made to homogenize the current territorial organization.
Subject(s)
Brain Ischemia , Ischemic Stroke , Stroke , Humans , Fibrinolytic Agents , Thrombolytic Therapy , Ischemic Stroke/epidemiology , Ischemic Stroke/surgery , Thrombectomy , Brain Ischemia/epidemiology , Brain Ischemia/surgery , Retrospective Studies , Treatment Outcome , Stroke/epidemiology , Stroke/surgery , Italy/epidemiologyABSTRACT
In this study, we report the first example of a photoswitchable copper complex with catechol oxidase activity. The distance between the two copper centres is optimal for catalytic catechol oxidation in the Z-configuration. Thus, the activity of the catalyst is increased compared to its E-configuration.
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BACKGROUND AND OBJECTIVES: The goal of this work was to investigate the natural history and outcomes after treatment for spontaneous amyloid-related imaging abnormalities (ARIA)-like in cerebral amyloid angiopathy-related inflammation (CAA-ri). METHODS: This was a multicenter, hospital-based, longitudinal, prospective observational study of inpatients meeting CAA-ri diagnostic criteria recruited through the Inflammatory Cerebral Amyloid Angiopathy and Alzheimer's Disease ßiomarkers International Network from January 2013 to March 2017. A protocol for systematic data collection at first-ever presentation and at subsequent in-person visits, including T1-weighted, gradient recalled echo-T2*, fluid-suppressed T2-weighted (fluid-attenuated inversion recovery), and T1 postgadolinium contrast-enhanced images acquired on 1.5T MRI, was used at the 3-, 6-, 12-, and 24-month follow-up. Centralized reads of MRIs were performed by investigators blinded to clinical, therapeutic, and time-point information. Main outcomes were survival, clinical and radiologic recovery, intracerebral hemorrhage (ICH), and recurrence of CAA-ri. RESULTS: The study enrolled 113 participants (10.6% definite, 71.7% probable, and 17.7% possible CAA-ri). Their mean age was 72.9 years; 43.4% were female; 37.1% were APOEε4 carriers; 36.3% had a history of Alzheimer disease; and 33.6% had a history of ICH. A history of ICH and the occurrence of new ICH at follow-up were more common in patients with cortical superficial siderosis at baseline (52.6% vs 14.3%, p < 0.0001 and 19.3% vs 3.6%, p < 0.009, respectively). After the first-ever presentation of CAA-ri, 70.3% (95% confidence interval [CI] 61.6%-78.5%) and 84.1% (95% CI 76.2%-90.6%) clinically recovered within 3 and 12 months, followed by radiologic recovery in 45.1% (95% CI 36.4%-54.8%) and 77.4% (95% CI 67.7%-85.9%), respectively. After clinicoradiologic resolution of the first-ever episode, 38.3% (95% CI 22.9%-59.2%) had at least 1 recurrence within the following 24 months. Recurrence was more likely if IV high-dose corticosteroid pulse therapy was suddenly stopped compared to slow oral tapering off (hazard ratio 4.68, 95% CI 1.57-13.93; p = 0.006). DISCUSSION: These results from the largest longitudinal cohort registry of patients with CAA-ri support the transient and potentially relapsing inflammatory nature of the clinical-radiologic acute manifestations of the disease and the effectiveness of slow oral tapering off after IV corticosteroid pulse therapy in preventing recurrences. Our results highlight the importance of differential diagnosis for spontaneous ARIA-like events in ß-amyloid-driven diseases, including treatment-related ARIA in patients with Alzheimer disease exposed to immunotherapy drugs.
Subject(s)
Cerebral Amyloid Angiopathy , Aged , Cerebral Amyloid Angiopathy/complications , Cerebral Amyloid Angiopathy/diagnostic imaging , Cerebral Hemorrhage , Cohort Studies , Female , Humans , Inflammation , Longitudinal Studies , Magnetic Resonance Imaging , Prospective StudiesABSTRACT
BACKGROUND: Since its approval, the use of alteplase had been limited to patients aged ≤80 years. AIMS: TESPI trial had been designed to evaluate whether alteplase treatment within 3 h in patients with acute ischemic stroke aged >80 years resulted in favorable benefit/risk ratio compared with standard care. The meta-analysis of randomized controlled trials was updated to put findings in the context of all available evidence. METHODS: TESPI was a multicenter, open-label with blinded outcome evaluation, randomized, controlled trial. Main clinical endpoints were 90-day favorable functional outcome (mRS score 0-2) and mortality and symptomatic intracerebral hemorrhage. The trial was prematurely terminated for ethical reasons after publication of IST-3 trial which provided evidence of treatment benefit in elderly. RESULTS: Of the planned 600 patients, 191 (88 assigned to alteplase) were enrolled. Overall, 24/83 (28.9%) alteplase patients had a favorable outcome compared to 22/95 (23.2%) controls (non-significant absolute difference of 5.7% for alteplase; OR 1.35, 95% CI 0.69-2.64, P = 0.381). Rates of death were non-significantly lower in the alteplase patients (18.1% vs. 26.5%); rates of symptomatic intracerebral hemorrhage were similar between the two groups (5.9% vs. 5.1%). The updated meta-analysis showed consistent results with prior estimates and add weights. CONCLUSIONS: The effects of alteplase observed in this interrupted trial did not reach statistical significance, probably for the small numbers, but are consistent with and add weight to the sum total of the randomized evidence demonstrating that alteplase is beneficial in patients with acute ischemic stroke aged over 80 years, particularly if given within 3 h.
Subject(s)
Brain Ischemia , Stroke , Aged , Brain Ischemia/complications , Brain Ischemia/drug therapy , Fibrinolytic Agents/therapeutic use , Humans , Italy , Multicenter Studies as Topic , Randomized Controlled Trials as Topic , Stroke/drug therapy , Thrombolytic Therapy , Tissue Plasminogen Activator/therapeutic use , Treatment OutcomeABSTRACT
Utilizing light is a smart way to fuel chemical transformations as it allows the energy to be selectively focused on certain molecules. Many reactions involving electronically excited species proceed via open-shell intermediates, which offer novel and unique routes to expand the hitherto used synthetic toolbox in organic chemistry. The direct conversion of non-prefunctionalized, less activated compounds is a highly desirable goal to pave the way towards more sustainable and atom-economic chemical processes. Photoexcited closed-shell anions have been shown to reach extreme potentials in single electron transfer reactions and reveal unusual excited-state reactivity. It is, therefore, surprising that their use as a reagent or photocatalyst is limited to a few examples. In this Review, we briefly discuss the characteristics of anionic photochemistry, highlight pioneering work, and show recent progress which has been made by utilizing photoexcited anionic species in organic synthesis.
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Herein is reported the asymmetric allylic benzylation of Morita-Baylis-Hillman (MBH) carbonates with 2-methylbenzophenone (MBP) derivatives as nonstabilized photogenerated C-nucleophiles. The dual activation of both reaction partners, chiral Lewis-base activation of the electrophile and light activation of the nucleophile, enables the stereoselective installation of benzyl groups at the allylic position to forge tertiary and quaternary carbon centers.
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In the present study, we investigate possible temporal impairment in patients with mild cognitive impairment (MCI) and the amount of temporal distortions caused by the presentation of emotional facial expressions (anger, shame, and neutral) in MCI patients and controls. Twelve older adults with MCI and 14 healthy older adults were enrolled in the present study. All participants underwent a complete neuropsychological evaluation. We used three timing tasks to tap temporal abilities, namely time bisection (standard intervals lasting 400 and 1600 ms), finger-tapping (free and 1 s), and simple reaction-time tasks. The stimuli used in the time bisection task were facial emotional stimuli expressing anger or shame to investigate a possible contribution of emotional information as previously observed in healthy adults. MCI patients showed temporal abilities comparable to controls. We observed an effect of facial emotional stimuli on time perception when data were analyzed in terms of proportion of long responses, and this result was mainly driven by the temporal overestimation when a facial expression of anger was presented in controls. Results seem to suggest that the severity of the cognitive dysfunction accounts more for subjective temporal impairment than a compromised internal clock.
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BACKGROUND: Patients with Alzheimer's disease (AD) present a typical biochemical profile of biomarkers: low concentration of ß amyloid 1-42 (Aß1-42), high concentration of total Tau (t-Tau) and phosphorylated Tau at threonine 181 (p-Tau). Several neurodegenerative diseases may overlap with AD, both in regards to clinical symptoms and neuropathology. Many data suggest that Alzheimer's disease (AD) pathophysiology can be identified using biomarkers. It has been hypothesized that subjects with dementia due to AD showed low levels of Aß1-42 combined with the highest levels of total Tau and phosphorylated Tau; moreover, it has been hypothesized that the ratio Aß1-42:p-Tau further help in discriminating Alzheimer's disease from other diagnoses. The aim of this work is to verify this hypothesis in our cohort of patients and to investigate if the same ratio could be a sensitive index able to discriminate MCI due to neurodegenerative factors (MCId) from MCI due to vascular factors (MCIv). METHODS: Two hundred sixty-two patients meeting the NIA-AA and NINDS-AIREN criteria were diagnosed as follow: AD in 120 patients [mean age 71.6 (42 - 87)], FTD in 23 patients [mean age 67.3 (46 - 78)], LBD in 17 patients [mean age 73.2 (58 - 83)], VAD in 9 patients [mean age 71.2 (60 - 81)]. According to the criteria proposed by Petersen RC, 24 patients had the diagnosis of MCId [mean age 71.8 (59 - 81)], 38 MCIv [mean age 69.3 (55-82). The comparison between the ratio of Aß1-42/p-Tau among the six groups was done using t-test for independent samples. A p-value < 0.05 was considered to represent statistical significance. The ROC (Receiver Operating Characteristic) curve analysis was made using R-studio software. RESULTS: The ratio Aß1-42:p-Tau was significantly lower in AD and MCId with respect to all the other groups and the difference was also statistically significant between MCId and MCIv. CONCLUSIONS: Aß1-42:p-Tau ratio has potential for being implemented in the clinical routine for differential diagnosis between AD and other dementias and to distinguish underling pathology such as neurodegenerative or vascular disease.
Subject(s)
Alzheimer Disease/diagnosis , Amyloid beta-Peptides/analysis , Biomarkers/analysis , Peptide Fragments/analysis , tau Proteins/analysis , Adult , Aged , Aged, 80 and over , Alzheimer Disease/metabolism , Cohort Studies , Diagnosis, Differential , Female , Humans , Male , Middle Aged , Neurodegenerative Diseases/diagnosis , Neurodegenerative Diseases/metabolism , Phosphorylation , ROC Curve , tau Proteins/metabolismABSTRACT
BACKGROUND: Dimethyl fumarate (DMF) is approved as first line therapy for relapsing-remitting multiple sclerosis (RRMS). In some (3%) patients, DMF induces a marked lymphopenia. Herpes simplex encephalitis (HSE) may occur in lymphopenic subjects under treatment with immune-suppressive drugs. CASE PRESENTATION: We report a case of a 39-year-old female patient with RRMS that developed HSE temporally associated with a marked and sudden drop in lymphocyte count, from 1200/µl to 600/µl, in the peripheral blood. HSE DNA was demonstrated in the cerebrospinal fluid. HSE had the features that characterize HSE occurring in immunosuppressed subjects, i.e. less prominent CSF pleocytosis, bilateral and mainly cortical involvement and less extensive tissue necrosis. Antiviral therapy determined a progressive, although incomplete, improvement. Three months later the patient presented only a mild short-term memory deficit and sporadic episodes of inappropriate emotionality. Lymphocyte count returned to normal values (1120/µl) after DMF discontinuation. CONCLUSION: Our case of HSE in a lymphopenic DMF-treated RRMS patient, points out the necessity of further studies on DMF-related lymphopenia, especially whether it implies an impaired immunity against viruses.
Subject(s)
Dimethyl Fumarate/adverse effects , Encephalitis, Herpes Simplex/etiology , Herpesvirus 1, Human/pathogenicity , Immunosuppressive Agents/adverse effects , Lymphopenia/chemically induced , Lymphopenia/complications , Multiple Sclerosis, Relapsing-Remitting/drug therapy , Adult , Female , HumansABSTRACT
This document presents the guidelines for testing antibodies against neuronal surface antigens that have been developed following a consensus process built on questionnaire-based surveys, internet contacts, and discussions at workshops of the sponsoring Italian Association of Neuroimmunology (AINI) congresses. Essential clinical information on autoimmune encephalitis associated with antibodies against neuronal surface antigens, indications and limits of testing for such antibodies, instructions for result interpretation, and an agreed laboratory protocol (Appendix A) are reported for the communicative community of neurologists and clinical pathologists.
Subject(s)
Antibodies/metabolism , Antigens, Surface/immunology , Encephalitis/diagnosis , Hashimoto Disease/diagnosis , Nerve Tissue Proteins/immunology , Humans , Models, MolecularABSTRACT
BACKGROUND: The new proposed diagnostic criteria for early diagnosis of Alzheimer's Disease (AD) underline the value of cerebrospinal fluid (CSF) biomarkers. The first aim of the study was to determine the diagnostic accuracy of CSF biomarker Abeta1-42, T-tau, and P-tau in differentiating AD patients in our cohort by means of "pure" biomarkers and in form of a combined analysis of these biomarkers. The second aim of the study was to determine the diagnostic accuracy of these markers for predicting incipient AD in patients with mild cognitive impairment (MCI). METHODS: We studied 102 CSF samples: 33 AD [mean age at baseline 71.2 (54-86)], 16 MCI [mean age at baseline 71.3 (57-78)], 24 non AD dementia, including 7 vascular dementia, 4 frontotemporal degeneration, 5 dementia with Lewy Body, and 8 with other dementia [mean age at baseline 72.7 (51-87)] and 32 non-demented neurological patients [mean age at baseline 71.3 (45-87) referred to as control (CO) later in the text]. A double sandwich ELISA (Innotest beta amyloid Abeta1-42, hTau and P-tau181 by Innogenetics, Gent, Belgium) was performed to quantify the concentration of the above biomarkers. The three biomarkers were then combined in the IATI index [(measured Ab1-42)/(240 + 1.18 *measured tau)], and in the ratios Abeta1-42/T-tau, Abeta1-42/P-tau, T-tau/Abeta1-42 and P-tau/Abeta1-42. RESULTS: Abeta1-42, T-tau and P-tau181 concentration showed statistically significant differences between AD and CO (327.2 pg/mL +/- 150.2 pg/mL and 659.4 pg/mL +/- 254.2 pg/mL; 508.2 pg/mL +/- 360.2 pg/mL and 305.3 pg/mL +/- 228.9 pg/mL; 82.2 pg/mL +/- 26.1 pg/mL and 45.3 pg/mL +/- 26.4 pg/mL, respectively, p < 0.05), while the difference between AD and MCI was statistically different only for Abeta1-42 (327.2 pg/mL +/- 150.2 pg/mL and 600.8 +/- 271.9 pg/mL, respectively, p < 0.05). The IATI index was 0.5 +/- 0.3 in AD, 0.9 +/- 0.6 in MCI, 1.37 +/- 0.9 in non AD dementia and 1.26 +/- 0.8 in non-demented neurological patients. With a cut-off fixed at 1 the sensitivity and specificity of the IATI index in discriminating AD from CO was 84% and 52%, respectively. CONCLUSIONS: This study confirms the great significance of CSF biomarker measurements in AD diagnosis in clinical routine. It is understood that a clinical diagnostic work-up is necessary in the process. Moreover, a biochemical profile of CSF biomarkers requires further investigations.
Subject(s)
Alzheimer Disease/cerebrospinal fluid , Amyloid beta-Peptides/cerebrospinal fluid , tau Proteins/cerebrospinal fluid , Aged , Aged, 80 and over , Alzheimer Disease/diagnosis , Biomarkers/cerebrospinal fluid , Humans , Middle AgedABSTRACT
The frequency and risk factors for intracerebral haemorrhage (ICH) after ischemic stroke are well-known. ICH frequency is increased by the use of antithrombotic or thrombolytic drugs. Several experimental studies have demonstrated a relationship between ICH and hypertension after fibrinolysis, but the optimal blood pressure levels in patients treated with recombinant tissue plasminogen activator (rTPA) are as yet unknown. We evaluated the role of blood pressure in patients with ischemic stroke treated with rTPA within 3h of symptom onset. We treated 86 consecutive patients admitted to our stroke unit between 2002 and 2008 and prospectively recorded the clinical and instrumental data in our stroke registry. We evaluated haemorrhagic complications by reviewing imaging findings. Blood pressure was recorded before rTPA and at 6, 12, 18, and 32h. Total cerebral haemorrhage occurred in eleven (12.7%) patients, and symptomatic intracerebral haemorrhage occurred in seven (8.1%). We failed to find a correlation between blood pressure levels and stroke severity at admission. High blood pressure levels correlated with a worse outcome. Systolic blood pressure was significantly higher in ICH patients relative to rTPA-treated patients without haemorrhagic complications (p<0.03). This study indicates that rTPA-induced haemorrhage is influenced by systolic blood pressure. More aggressive pharmacological reduction of hypertension during fibrinolysis and the subsequent 32h may reduce this complication.