Comparison of 6 tests for diagnosing minimal hepatic encephalopathy and predicting clinical outcome: A prospective, observational study.

BACKGROUND AND AIMS: Current guidelines recommend the assessment for minimal HE in patients with liver cirrhosis. Various efforts were made to find tools that simplify the diagnosis. Here, we compare the 6 most frequently used tests for their validity and their predictive value for overt hepatic encephalopathy (oHE), rehospitalization, and death. APPROACH AND RESULTS: One hundred thirty-two patients with cirrhosis underwent the Portosystemic Encephalopathy-Syndrome-Test yielding the psychometric hepatic encephalopathy score (PHES), Animal Naming Test (ANT), Critical Flicker Frequency (CFF), Inhibitory Control Test (ICT), EncephalApp (Stroop), and Continuous Reaction Time Test (CRT). Patients were monitored for 365 days regarding oHE development, rehospitalization, and death. Twenty-three patients showed clinical signs of HE grade 1-2 at baseline. Of the remaining 109 neurologically unimpaired patients, 35.8% had abnormal PHES and 44% abnormal CRT. Percentage of abnormal Stroop (79.8% vs. 52.3%), ANT (19.3% vs. 51.4%), ICT (28.4% vs. 36.7%), and CFF results (18.3% vs. 25.7%) changed significantly when adjusted norms were used for evaluation instead of fixed cutoffs. All test results correlated significantly with each other ( p <0.05), except for CFF. During follow-up, 24 patients developed oHE, 58 were readmitted to the hospital, and 20 died. Abnormal PHES results were linked to oHE development in the multivariable model. No other adjusted test demonstrated predictive value for any of the investigated endpoints. CONCLUSIONS: Where applicable, the diagnosis of minimal HE should be made based on adjusted norm values for the tests, exclusively. The minimal HE tests cannot be equated with one another and have an overall limited value in predicting clinical outcomes.

Ethnic diversity in presentation and outcome of Waldenström macroglobulinemia and IgM monoclonal gammopathy of clinical significance in the United Kingdom.

Not available.

Butyrylcholinesterase activity in patients with postoperative delirium after cardiothoracic surgery or percutaneous valve replacement- an observational interdisciplinary cohort study.

BACKGROUND AND OBJECTIVES: Postoperative delirium is a frequent and severe complication after cardiac surgery. Activity of butyrylcholinesterase (BChE) has been discussed controversially regarding a possible role in its development. This study aimed to investigate the relevance of BChE activity as a biomarker for postoperative delirium after cardiac surgery or percutaneous valve replacement. METHODS: A total of 237 patients who received elective cardiothoracic surgery or percutaneous valve replacement at a tertiary care centre were admitted preoperatively. These patients were tested with the Montreal Cognitive Assessment investigating cognitive deficits, and assessed for postoperative delirium twice daily for three days via the 3D-CAM or the CAM-ICU, depending on their level of consciousness. BChE activity was measured at three defined time points before and after surgery. RESULTS: Postoperative delirium occurred in 39.7% of patients (n = 94). Univariate analysis showed an association of pre- and postoperative BChE activity with its occurrence (p = 0.037, p = 0.001). There was no association of postoperative delirium and the decline in BChE activity (pre- to postoperative, p = 0.327). Multivariable analysis including either preoperative or postoperative BChE activity as well as age, MoCA, type 2 diabetes mellitus, coronary heart disease, type of surgery and intraoperative administration of red-cell concentrates was performed. Neither preoperative nor postoperative BChE activity was independently associated with the occurrence of postoperative delirium (p = 0.086, p = 0.484). Preoperative BChE activity was lower in older patients (B = -12.38 (95% CI: -21.94 to -2.83), p = 0.011), and in those with a history of stroke (B = -516.173 (95% CI: -893.927 to -138.420), p = 0.008) or alcohol abuse (B = -451.47 (95% CI: -868.38 to -34.55), p = 0.034). Lower postoperative BChE activity was independently associated with longer procedures (B = -461.90 (95% CI: -166.34 to -757.46), p = 0.002), use of cardiopulmonary bypass (B = -262.04 (95% CI: -485.68 to -38.39), p = 0.022), the number of administered red cell-concentrates (B = -40.99 (95% CI: -67.86 to -14.12), p = 0.003) and older age (B = -9.35 (95% CI: -16.04 to -2.66), p = 0.006). CONCLUSION: BChE activity is not independently associated with the occurrence of postoperative delirium. Preoperative BChE values are related to patients' morbidity and vulnerability, while postoperative activities reflect the severity, length and complications of surgery.

Assessment of associations between neutrophil extracellular trap biomarkers in blood and thrombi in acute ischemic stroke patients.

Inflammation including immunothrombosis by neutrophil extracellular traps (NETs) has important implications in acute ischemic stroke and can affect reperfusion status, susceptibility to stroke associated infections (SAI) as well as functional clinical outcome. NETs were shown to be prevalent in stroke thrombi and NET associated markers were found in stroke patients' blood. However, little is known whether blood derived NET markers reflect the amount of NETs in thrombi. Conclusions from blood derived markers to thrombus composition might open avenues for novel strategies in diagnostic and therapeutic approaches. We prospectively recruited 166 patients with acute ischemic stroke undergoing mechanical thrombectomy between March 2018 and May 2021. Available thrombi (n = 106) were stained for NET markers DNA-histone-1 complexes and myeloperoxidase (MPO). Cell free DNA (cfDNA), deoxyribonuclease (DNase) activity, MPO-histone complexes and a cytokine-panel were measured before thrombectomy and after seven days. Clinical data, including stroke etiology, reperfusion status, SAI and functional outcome after rehabilitation, were collected of all patients. NET markers were present in all thrombi. At onset the median concentration of cfDNA in blood was 0.19 µg/ml increasing to 0.30 µg/ml at 7 days. Median DNase activity at onset was 4.33 pmol/min/ml increasing to 4.96 pmol/min/ml at 7 days. Within thrombi DNA-histone-1 complexes and MPO correlated with each other (ρ = 0.792; p < 0.001). Moreover, our study provides evidence for an association between the amount of NETs and endogenous DNase activity in blood with amounts of NETs in cerebral thrombi. However, these associations need to be confirmed in larger cohorts, to investigate the potential clinical implications for individualized therapeutic and diagnostic approaches in acute ischemic stroke.

Prevalence of Minimal Hepatic Encephalopathy in Patients With Liver Cirrhosis: A Multicenter Study.

INTRODUCTION: The prevalence of minimal hepatic encephalopathy (MHE), in particular in different subgroups, remains unknown. This study aimed to analyze the prevalence of MHE in different subgroups to identify patients at high risk and to pave the way for personalized screening approaches. METHODS: In this study, data of patients recruited at 10 centers across Europe and the United States were analyzed. Only patients without clinical signs of hepatic encephalopathy were included. MHE was detected using the Psychometric Hepatic Encephalopathy Score (PHES, cut-off < or ≤-4 depending on local norms). Clinical and demographic characteristics of the patients were assessed and analyzed. RESULTS: In total, 1,868 patients with cirrhosis with a median model for end-stage liver disease (MELD) of 11 were analyzed (Child-Pugh [CP] stages: A 46%, B 42%, and C 12%). In the total cohort, MHE was detected by PHES in 650 patients (35%). After excluding patients with a history of overt hepatic encephalopathy, the prevalence of MHE was 29%. In subgroup analyses, the prevalence of MHE in patients with CP A was low (25%), whereas it was high in CP B or C (42% and 52%). In patients with a MELD score <10, the prevalence of MHE was only 25%, but it was 48% in patients with a MELD score ≥20. Standardized ammonia levels (ammonia level/upper limit of normal of each center) correlated significantly, albeit weakly with PHES (Spearman ρ = -0.16, P < 0.001). DISCUSSION: The prevalence of MHE in patients with cirrhosis was high but varied substantially between diseases stages. These data may pave the way for more individualized MHE screening approaches.

Iatrogenic cerebral amyloid angiopathy: An illustrative case of a newly introduced disease.

BACKGROUND AND PURPOSE: Iatrogenic cerebral amyloid angiopathy (iCAA) is a specific type of cerebral amyloid angiopathy which is becoming increasingly diagnosed. It has been hypothesized that iCAA might arise as a late consequence of past neurosurgical interventions involving dural patch grafts. Positron emission tomography (PET) scans with amyloid tracers and the assay of beta-amyloid levels in cerebrospinal fluid (CSF) are auxiliary criteria, however, definite diagnosis remains histopathologically determined. METHODS: Case report. RESULTS: We present a 48-year-old patient who suffered multiple lobar cerebral haemorrhages from the age of 47. The patient had undergone surgery for remolval of hemangioblastoma with lyophilized dural graft at the age of 11, in 1987. Brain MRI, amiloid PET and CSF analysis led to a diagnosis of probable iCAA. CONCLUSION: It is necessary to increase the awareness of iCAA, in order to avoid overlooking the potential causal involvement of surgical procedures which took place far back in time. Moreover, the diagnostic relevance of amyloid PET and beta-amyloid levels in CSF must be emphasised.

Outcomes of modular cable exchange in HeartMate 3 patients versus conventional driveline repair in HeartMate II patients.

BACKGROUND: Driveline (DL) damages are a common difficulty among ventricular assist devices (VAD). Repairing the electrical fibers inside the DL on a running pump is hazardous and requires technical expertise, which is not easily available on site. A new feature of the HeartMate3 (Abbott, U.S.A.) LVAD is a modular driveline that allows an easy exchange of the DL cord. In this report we analyze our experiences with this feature. METHODS: We performed a retrospective analysis of 302 patients who underwent either HeartMate II or HeartMate 3 implantation between February 2004 and September 2021. Patients were screened for driveline faults and need for exchange or repair of driveline or VAD exchange. Documented were baseline characteristics, reasons for DL or VAD exchange, and complications. Follow-up was three months after the procedure. RESULTS: We present a cohort of 302 patients who underwent either HMII (n = 107;35.4%) or HM 3 (n = 195; 64.5%) implantation. Out of those, 40 patients (40/302; 13.2%) required driveline repair (DLRe) or exchange (DLEx). Out of 107 HMII patients, 9 showed severe DL damages (9/107; 8.4%). Six patients (6/9; 66.6%) underwent DLRe, two patients (2/6; 33.3%) required VAD exchange after DLRe, one patient (1/2;50%) experienced emergency VAD exchange after pump stop. The DLRe procedure in the other four patients (4/6; 66.6%) was successful. Due to damage to the internal driveline two patients (2/9; 22.2%) underwent emergency device exchange and one patient (1/9;11.1%) was listed for transplantation. 31 out 195 HM3 patients underwent exchange of the modular DL. In none of the cases, damages of the internal fibers were the reasons for the exchange. In 100% of the cases, damages of the external coating were the reason for DL exchange. In none of the cases, complications occurred after the exchange procedure. CONCLUSIONS: Driveline damages are a habitual, recurrent complication in VAD patients. The exchange of the modular driveline cable of the HM3 is feasible and safe compared to the conventional DL repair in HMII patients. Risky repair attempts and surgical LVAD exchange due to major damages of the electrical fibers can be avoided successfully by the new feature of HM3 driveline.

Microembolic signal monitoring in patients with HeartMate 3 and HeartWare left ventricular assist devices: Association with antithrombotic treatment and cerebrovascular events.

BACKGROUND: In patients with left ventricular assist devices (LVADs), ischemic and hemorrhagic stroke are dreaded complications. Predictive markers for these events are lacking. This study aimed to investigate the prevalence and predictive value of microembolic signals (MES) for stroke, detected by Transcranial Doppler sonography (TCD) in patients with HeartMate 3 (HM 3) or HeartWare (HW). METHODS: A thirty-minute bilateral TCD monitoring of the middle cerebral artery (MCA) was performed in 62 outpatients with LVAD (HM 3 N = 31, HW N = 31) and 31 healthy controls. Prevalence and quantity of MES were investigated regarding clinical and laboratory parameters. Cerebrovascular events (CVE) were recorded on follow-up at 90 and 180 days. RESULTS: MES were detected in six patients with HM 3, three patients with HW, and three controls. Within the LVAD groups, patients on monotherapy with vitamin-K-antagonist (VKA) without antiplatelet therapy were at risk for a higher count of MES (negative binomial regression: VKA: 1; VKA + ASA: Exp(B) = 0.005, 95%CI 0.001-0.044; VKA + clopidogrel: Exp(B) = 0.012, 95%CI 0.002-0.056). There was no association between the presence of MES and CVE or death on follow-up (p > 0.05). CONCLUSION: For the first time, the prevalence of MES was prospectively investigated in a notable outpatient cohort of patients with HM 3 and HW. Despite optimized properties of the latest LVAD, MES remain detectable depending on antithrombotic therapy. No association between MES and CVE could be detected.

Smart Inhibition Action of Amino Acid-Modified Layered Double Hydroxide and Its Application on Carbon Steel.

Surface impregnation of concrete structures with a migrating corrosion inhibitor is a promising and non-invasive technique for increasing the lifetime of existing structures that already show signs of corrosion attack. The main requirement for inhibitors is their ability to diffuse the rebar at a sufficient rate to protect steel. The use of smart nanocontainers such as layered double hydroxides (LDH) to store corrosion inhibitors significantly increases efficiency by providing an active protection from chloride-induced corrosion. The addition of LDH to reinforced mortar can also improve the compactness and mechanical properties of this matrix. Here, we report the synthesis of a magnesium-aluminum LDH storing glutamine amino acid as a green inhibitor (labeled as Mg-Al-Gln), which can be used as a migrating inhibitor on mortar specimens. The corrosion behavior of the specimens was determined via electrochemical techniques based on measurements of corrosion potential and electrochemical impedance spectroscopy. A cell containing a 3.5% NaCl solution was applied to the mortar surface to promote the corrosion of embedded rebars. The specimens treated with Mg-Al-Gln presented an improved corrosion protection performance, exhibiting an increase in polarization resistance (Rp) compared to the reference specimens without an inhibitor (NO INH). This effect is a consequence of a double mechanism of protection/stimuli-responsive release of glutamine and the removal of corrosive chloride species from the medium.

Endogenous Deoxyribonuclease Activity and Cell-Free Deoxyribonucleic Acid in Acute Ischemic Stroke: A Cohort Study.

BACKGROUND: Cell-free DNA (cfDNA) and endogenous deoxyribonuclease activity are opposing mediators and might influence the inflammatory response following acute ischemic stroke. In this cohort study, we investigated the relation between these markers, circulating inflammatory mediators and clinical course including occurrence of stroke-associated infections (SAI) in patients with acute stroke. METHODS: Ninety-two patients with stroke due to large vessel occlusion undergoing mechanical thrombectomy were prospectively recruited at Hannover Medical School from March 2018 to August 2019. Deoxyribonuclease activity, cfDNA, damage-associated molecular patterns, and circulating cytokines were measured in venous blood collected immediately before mechanical thrombectomy and 7 days later. Reperfusion status was categorized (sufficient/insufficient). Clinical outcome was evaluated using the modified Rankin Scale after 90 days, where a score of 3 to 6 was considered unfavorable. To validate findings regarding SAI, another stroke cohort (n=92) was considered with blood taken within 24 hours after stroke onset. RESULTS: Patients with unfavorable clinical outcome had higher cfDNA concentrations. After adjustment for confounders (Essen Stroke Risk Score, National Institutes of Health Stroke Scale, and sex), 7-day cfDNA was independently associated with clinical outcome and especially mortality (adjusted odds ratio: 3.485 [95% CI, 1.001-12.134] and adjusted odds ratio: 9.585 [95% CI, 2.006-45.790]). No association was found between reperfusion status and cfDNA or deoxyribonuclease activity. While cfDNA concentrations correlated positively, deoxyribonuclease activity inversely correlated with distinct biomarkers. Baseline deoxyribonuclease activity was lower in patients who developed SAI compared with patients without SAI. This association was confirmed after adjustment for confounding factors (adjusted odds ratio: 0.447 [95% CI, 0.237-0.844]). In cohort 2, differences of deoxyribonuclease activity between patients with and without SAI tended to be higher with higher stroke severity. CONCLUSIONS: The interplay of endogenous deoxyribonuclease activity and cfDNA in acute stroke entails interesting novel diagnostic and potential therapeutic approaches. We confirm an independent association of cfDNA with a detrimental clinical course after stroke due to large vessel occlusion. This study provides first evidence for lower endogenous deoxyribonuclease activity as risk factor for SAI after severe stroke.

Risk of acute kidney injury after contrast-enhanced computerized tomography: a systematic review and meta-analysis of 21 propensity score-matched cohort studies.

OBJECTIVES: Intravenous application of contrast media is part of a wide spectrum of diagnostic procedures for better imaging quality. Clinical avoidance of contrast-enhanced imaging is an ever-present quandary in patients with impaired kidney function. The objective of this study was to estimate the risk for acute kidney injury (AKI), dialysis and mortality among patients undergoing contrast-enhanced CT compared to propensity score-matched controls (i.e. contrast-unenhanced CT). Selected cohort studies featured high-risk patients with advanced kidney disease and critical illness. METHODS: This review was designed to conform to the Preferred Reporting Items in Systematic Reviews and Meta-Analysis (PRISMA) guidelines. PubMed was searched from August 2021 to November 2021 for all-language articles without date restriction. A random-effects model (DerSimonian and Laird method) was used for meta-analysis. RESULTS: Twenty-one articles were included, comprising data of 169,455 patients. The overall risk of AKI was similar in the contrast-enhanced and unenhanced groups (OR: 0.97 [95% CI: 0.85; 1.11], p = 0.64), regardless of baseline renal function and underlying disease. Substantial heterogeneity was detected (I2 = 90%, p ≤ 0.0001). Multivariable logistic regression identified hypertension (p = 0.03) and estimated glomerular filtration rate (eGFR) ≤ 30 mL/min/1.73 m2 (p = 0.0001) as factors associated with greater risk of post-contrast AKI. CONCLUSIONS: Based on propensity score-matched pairs obtained from 21 cohort studies, we found no evidence for increased risk for AKI, dialysis or mortality after contrast-enhanced CT among patients with eGFR ≥ 45 mL/min/1.73 m2. In congruence with the emerging evidence in the literature, caution should be exercised in patients with hypertension and eGFR ≤ 30 mL/min/1.73 m2. KEY POINTS: • The application of contrast media for medical imaging is not associated with higher odds for AKI, induction of renal replacement therapy, or mortality. Many comorbidities traditionally associated with greater risk for acute kidney injury do not appear to predispose for renal decline after contrast media exposure. • Underlying hypertension and eGFR less than or equal to 30 mL/min/1.73 m2 seem to predispose for post-contrast acute kidney injury. • Propensity score matching cannot account for unmeasured influences on AKI incidence, which needs to be addressed in the interpretation of results.

Circulating Inflammatory Biomarkers in Early Prediction of Stroke-Associated Infections.

(1) Background: Patients with acute ischaemic stroke (AIS) are at high risk for stroke-associated infections (SAIs). We hypothesised that increased concentrations of systemic inflammation markers predict SAIs and unfavourable outcomes; (2) Methods: In 223 patients with AIS, blood samples were taken at ≤24 h, 3 d and 7d after a stroke, to determine IL-6, IL-10, CRP and LBP. The outcome was assessed using the modified Rankin Scale at 90 d. Patients were thoroughly examined regarding the development of SAIs; (3) Results: 47 patients developed SAIs, including 15 lower respiratory tract infections (LRTIs). IL-6 and LBP at 24 h differed, between patients with and without SAIs (IL-6: p < 0.001; LBP: p = 0.042). However, these associations could not be confirmed after adjustment for age, white blood cell count, reduced consciousness and NIHSS. When considering the subgroup of LRTIs, in patients who presented early (≤12 h after stroke, n = 139), IL-6 was independently associated with LRTIs (OR: 1.073, 95% CI: 1.002−1.148). The ROC-analysis for prediction of LRTIs showed an AUC of 0.918 for the combination of IL-6 and clinical factors; (4) Conclusions: Blood biomarkers were not predictive for total SAIs. At early stages, IL-6 was independently associated with outcome-relevant LRTIs. Further studies need to clarify the use of biochemical markers to identify patients prone to SAIs.

Toward a Green and Sustainable Silver Conservation: Development and Validation of Chitosan-Based Protective Coatings.

When exposed to air, silver artifacts undergo an unpleasant darkening and shiny loss, commonly known as tarnishing. At the present, the development of protective coatings by using eco-friendly and biocompatible materials, able to ensure high transparency and to hinder the degradation of silver objects, remains a huge challenge. In this study, chitosan was used for the first time to realize sustainable coatings for silver protection. Both pure and benzotriazole-containing chitosan coatings were prepared and applied on sterling silver disks. A commercial product based on acrylic resin was used as a reference. The aesthetic features and protective properties of these coatings were evaluated by performing two different types of aging treatments. In particular, the assessment of the protective efficacy was carried out by reproducing both highly aggressive polluted environments and real-like museums' storage conditions. In the first case, chitosan-based coatings with benzotriazole performed better, whereas in storage conditions all the chitosan films showed comparable efficacy. Compositional, morphological and structural analyses were used to evaluate the protective properties of the coatings and to detect any physical or chemical modifications after the aging treatments. Our findings reveal that the two different testing methods provide complementary information. Moreover, chitosan coatings can achieve protective efficacy comparable with that of the commercial product but using non-toxic solvents and a renewable biopolymer. Chitosan coatings, designed for cultural heritage conservation, are thus promising for the protection of common sterling silver objects.

Autoantibodies against the NMDAR subunit NR1 are associated with neuropsychiatric outcome after ischemic stroke.

BACKGROUND AND PURPOSE: Preexisting autoantibodies against N-methyl-D-aspartate-receptor subunit NR1 (NMDAR1-AB) in acute ischemic stroke patients with previously intact blood-brain-barrier were associated with smaller evolution of lesion size. Effects of chronic exposure to NMDAR1-AB long after stroke, however, have remained unclear. We investigated in a prospective follow-up study whether long-term neuropsychiatric outcome after stroke differs depending on NMDAR1-AB status. METHODS: Blood samples for NMDAR1-AB analysis were collected within 24 h after ischemic stroke from n = 114 patients. Outcome was assessed 1-3 years later using NIHSS, modified Rankin-scale, Barthel-Index, RBANS (Repeatable Battery for the Assessment of Neuropsychological Status) subcategories (immediate/delayed memory, attention, visuoconstruction), anamnesis evaluating neuropsychiatric symptoms (e.g. hallucinations, psychomotor slowing, reduced alertness, depressiveness, fatigue) and questionnaires (Beck's Depression Inventory-BDI, Fatigue Impact Scale-FIS). Scores were generated to cover RBANS plus neuropsychiatric symptoms (Score A; n = 96) or only neuropsychiatric symptoms (Score B; n = 114, including patients unable to conduct RBANS). Depression/fatigue were measured in patients, capable to perform questionnaires (n = 86). RESULTS: NMDAR1-AB (IgM, IgA, IgG) were detected in n = 27 patients (23.7%). NMDAR1-AB seropositive patients showed inferior results in Score A (p = 0.006), Score B (p = 0.004), BDI (p = 0.013) and FIS (p = 0.018), compared to seronegative patients. Multiple regression analysis including covariates age, NIHSS at day 7 post-stroke, and days from stroke to follow-up, showed NMDAR1-AB seropositivity associated with worse outcome in Scores A (b: 1.517, 95%CI: 0.505-2.529, p = 0.004) and B (b: 0.803, 95%CI: 0.233-1.373; p = 0.006). Also FIS was unfavorably associated with NMDAR1-AB seropositivity (binary logistic regression: OR: 3.904, 95%CI: 1.200-12.695; p = 0.024). CONCLUSIONS: Even though the numbers of included patients are low, our data apparently indicate that NMDAR1-AB seropositivity at the time point of acute ischemic stroke is associated with neuropsychiatric symptoms including cognitive dysfunction and fatigue years after stroke. Preclinical proof of a causal relation provided, targeted immunosuppression may be a future prophylactic option to be clinically evaluated.

Nonstenotic Carotid Plaque in Embolic Stroke of Undetermined Source: Interplay of Arterial and Atrial Disease.

BACKGROUND AND PURPOSE: Approximately one-sixth of all ischemic strokes are attributable to embolic stroke of undetermined source (ESUS). Recent analyses suggest that atrial cardiopathy and nonstenotic carotid plaque (nsCP) may represent 2 distinct underlying causes in patients with ESUS, although both diseases share common risk factors and are pathophysiologically intertwined. In this study, we, therefore, aimed to search for associations between nsCP and markers of atrial remodeling and function in patients with embolic stroke. METHODS: Sixty-eight patients with ESUS or atrial fibrillation (AF)-related stroke proven by imaging who underwent comprehensive echocardiographic studies, including measurements of left atrial function and remodeling, were considered. Patients with ESUS underwent a follow-up of at least 1 year after index stroke. For 20 patients with ESUS, NT-proBNP (N-terminal pro-B-type natriuretic peptide) values were available. Presence of nsCP was evaluated considering Duplex sonography and computed tomography angiography and was further categorized in possibly or probably symptomatic nsCP. RESULTS: ESUS patients with nsCP tended to have higher values of septal and lateral total atrial conduction times (P=0.071 and P=0.072, respectively), left atrial volume index (P=0.077), and revealed significantly higher strain rates during early diastole (P=0.013) as well as higher NT-proBNP values (P=0.010) than ESUS patients without nsCP. Moreover, septal total atrial conduction time was significantly longer in ESUS patients with possibly symptomatic nsCP compared with those without (P=0.015). Comparison of ESUS with AF patients revealed significantly higher proportions of nsCP (P=0.010), possibly symptomatic nsCP (P=0.037), and probably symptomatic nsCP (P=0.036) in patients with atrial fibrillation-related stroke. In the regression analysis adjusted for vascular risk factors probably symptomatic nsCP remained significantly associated with AF (P=0.048, odds ratio: 4.46 [95% CI, 1.02-19.56]). CONCLUSIONS: Presence of nsCP is associated with AF and markers of left atrial disease in patients with embolic stroke. Therefore, a thorough evaluation regarding atrial cardiopathy and AF in patients with ESUS should not be restricted if nsCP are found, even if high-risk plaque characteristics are evident.

Plasma Dimethylarginine Levels and Carotid Intima-Media Thickness are related to Atrial Fibrillation in Patients with Embolic Stroke.

A relevant part of embolic strokes of undetermined source (ESUS) is assumed to be due to non-detected atrial fibrillation (AF). In this study, we aimed to investigate if markers of endothelial dysfunction and damage may indicate AF risk in embolic stroke. Eighty-eight patients with ischemic stroke confirmed by imaging were assigned to one of three groups: ESUS, AF, or micro-/macroangiopathy. ESUS patients underwent prolonged Holter electrocardiography scheduled for three days. The National Institutes of Health Stroke Scale (NIHSS), the CHA2DS2VASC score, and the carotid intima⁻media thickness (CIMT) were obtained. Markers of endothelial (dys)function (L-arginine, asymmetric dimethylarginine (ADMA), symmetric dimethylarginine (SDMA)) were measured at day seven after stroke. ESUS patients were younger and had fewer cardiovascular risk factors than patients with determined stroke etiology. Compared with AF patients, ESUS patients showed significantly lower values of SDMA (p = 0.004) and higher values of L-arginine (p = 0.031), L-arginine/ADMA ratio (p = 0.006), L-arginine/SDMA ratio (p = 0.002), and ADMA/SDMA ratio (p = 0.013). Concordant differences could be observed comparing ESUS patients with those with newly diagnosed AF (p = 0.026; p = 0.03; p = 0.009; p = 0.004; and p = 0.046, respectively). CIMT was significantly larger in AF than in ESUS patients (p < 0.001), and was identified as an AF risk factor independent from CHA2DS2VASC in the regression analysis (p = 0.014). These findings may support future stratification for AF risk in patients who have suffered embolic stroke.

High-dose folic acid supplementation alters the human sperm methylome and is influenced by the MTHFR C677T polymorphism.

Dietary folate is a major source of methyl groups required for DNA methylation, an epigenetic modification that is actively maintained and remodeled during spermatogenesis. While high-dose folic acid supplementation (up to 10 times the daily recommended dose) has been shown to improve sperm parameters in infertile men, the effects of supplementation on the sperm epigenome are unknown. To assess the impact of 6 months of high-dose folic acid supplementation on the sperm epigenome, we studied 30 men with idiopathic infertility. Blood folate concentrations increased significantly after supplementation with no significant improvements in sperm parameters. Methylation levels of the differentially methylated regions of several imprinted loci (H19, DLK1/GTL2, MEST, SNRPN, PLAGL1, KCNQ1OT1) were normal both before and after supplementation. Reduced representation bisulfite sequencing (RRBS) revealed a significant global loss of methylation across different regions of the sperm genome. The most marked loss of DNA methylation was found in sperm from patients homozygous for the methylenetetrahydrofolate reductase (MTHFR) C677T polymorphism, a common polymorphism in a key enzyme required for folate metabolism. RRBS analysis also showed that most of the differentially methylated tiles were located in DNA repeats, low CpG-density and intergenic regions. Ingenuity Pathway Analysis revealed that methylation of promoter regions was altered in several genes involved in cancer and neurobehavioral disorders including CBFA2T3, PTPN6, COL18A1, ALDH2, UBE4B, ERBB2, GABRB3, CNTNAP4 and NIPA1. Our data reveal alterations of the human sperm epigenome associated with high-dose folic acid supplementation, effects that were exacerbated by a common polymorphism in MTHFR.

Evaluation of larvicidal activity and ecotoxicity of linalool, methyl cinnamate and methyl cinnamate/linalool in combination against Aedes aegypti.

The frequent use of synthetic pesticides to control Aedes aegypti population can lead to environmental and/or human contamination and the emergence of resistant insects. Linalool and methyl cinnamate are presented as an alternative to the synthetic pesticides, since they can exhibit larvicidal, repellent and/or insecticidal activity and are considered safe for use. The aim of this study was to evaluate the larvicidal activity of methyl cinnamate, linalool and methyl cinnamate/linalool in combination (MC-L) (1:4 ratio, respectively) against Aedes aegypti. The in vitro preliminary toxicity through brine shrimp lethality assay and hemolytic activity, and the phytotoxic potential were also investigated to assess the safety of their use as larvicide. Methyl cinnamate showed significant larvicidal activity when compared to linalool (LC50 values of 35.4µg/mL and 275.2µg/mL, respectively) and to MC-L (LC50 138.0µg/mL). Larvae morphological changes subjected to the specified treatments were observed, as the flooding of tracheal system and midgut damage, hindering the larval development and survival. Preliminary in vitro toxicity through brine shrimp showed the high bioactivity of the substances (methyl cinnamate LC50 35.5µg/mL; linalool LC50 96.1µg/mL) and the mixture (MC-L LC50 57.7µg/mL). The results showed that, despite the higher larvicidal activity of methyl cinnamate, the use of MC-L as a larvicide seems to be more appropriate due to its significant larvicidal activity and low toxicity.