Number Of Plaques Research Articles

The effect of minocycline on beta-amyloid-induced memory and learning deficit in male rats: A behavioral, biochemical, and histological study

ObjectivesMinocycline hydrochloride is a semi-synthetic, second-generation tetracycline with neuroprotective, neurorestorative, anti-amyloidogenic, anti-inflammatory, antioxidant, and anti-apoptotic properties. The present study was designed to investigate the potential protective effects of minocycline against beta-amyloid (Aβ)-induced Alzheimer’s disease (AD), recognition memory decline, and the possible involved anti-apoptotic mechanisms. MethodsThe rats were treated with minocycline (50 and 100 mg/kg/day; P.O.) after AD induction for 30 days. Behavioral functions were assessed by employing standard behavioral tests, including novel object recognition (NOR) and passive avoidance learning (PAL) tasks. Then, total antioxidant capacity (TAC) and total oxidant status (TOS) were measured in blood serum using ELISA kits. Apoptosis and the number of Aβ plaques were examined by the TUNEL and Congo red staining, respectively. ResultsTreatment of Aβ rats with minocycline improved memory deficit in the PAL task and a decline in recognition memory in the NOR test. Minocycline at 50 and 100 mg/kg significantly reduced the TOS levels and increased the TAC levels (P < 0.0001). Also, minocycline at 50 and 100 mg/kg reduced the apoptotic index in the hippocampus of Aβ rats. After Congo red staining, the minocycline group showed improved cell morphology and markedly fewer Aβ plaques. ConclusionsMinocycline reduced memory and learning deficit in behavioral experiments after Aβ injection, which may be due to its anti-inflammatory and anti-apoptotic effects.

Determinants of left ventricular diastolic dysfunction in hemodialysis patients

Introduction: Chronic kidney disease (CKD) induces changes in the myocardium known to influence morbidity and mortality, most severe in patients with end stage renal disease. Objectives: The working hypothesis was that in patients on chronic hemodialysis the prevalence of left ventricular diastolic dysfunction is correlated with the inflammatory, oxidative, metabolic, nutritional, and atherosclerotic status. Patients and Methods: An observational study was performed on 51 patients (age 59.76 ± 13.24 years) on hemodialysis treatment. Transthoracic cardiac ultrasound was conducted to evaluate LVDD. The burden of cardiac and arterial atherosclerosis was evaluated by cardiac ultrasound (aortic and mitral valve calcifications), vascular ultrasound (carotid and femoral atheroma plaques, common carotid intima-media thickness), and by abdominal radiography (aortic calcification score). Demographic and anthropometric parameters were determined. Blood samples were used to determine laboratory parameters reflecting the inflammatory, oxidative, and metabolic/nutrition status. Results: LVDD is positively correlated with the serum level of C-reactive protein (CRP) (P=0.04), the total antioxidant capacity of the serum (P=0.04), the presence (P=0.022) and number (P=0.04) of femoral plaques, the aortic calcification score (P=0.02), aortic valve stenosis (P=0.037), aortic annulus calcifications (P=0.02) and mitral valve calcifications (P=0.041). After the removal of the main confounder, degenerative aortic stenosis, only the associations with serum total antioxidant capacity (P=0.04) and aortic calcification score (P= 0.02) maintain their statistical significance. Conclusion: LVDD is positively correlated with inflammation and oxidative stress markers and with the severity of aortic calcification.

Relationship Between Monocyte-to-Lymphocyte Ratio as Well as Other Leukocyte-Derived Ratios and Carotid Plaques in Patients with Coronary Heart Disease: A RCSCD-TCM Study.

PurposeThis study explored the relationship between monocyte-to-lymphocyte ratio (MLR) as well as other leukocyte-derived ratios and carotid plaques in patients with coronary heart disease (CHD).Patients and MethodsA total of 12,093 patients with CHD were selected as research participants. Leukocyte-derived ratios assessed in this study included neutrophil-to-lymphocyte ratio (NLR), derived NLR (dNLR), MLR, platelet-to-lymphocyte ratio (PLR), white blood cell-to-mean platelet volume ratio (WMR), lymphocyte×neutrophil/104 ratio (MNM), systemic immune inflammation index (SII), and systemic inflammation response index (SIRI). Leukocyte-derived ratios were divided into four groups according to quarters. Logistic regression analysis was performed to evaluate the relationship between leukocyte-derived ratios and the incidence, number, and echo characteristics of carotid plaques in patients with CHD. Further analysis was performed after adjusting for confounding factors.ResultsAmong the 12,093 participants, 71.7% had carotid plaques. After adjusting for confounding factors, MLR, NLR, dNLR, PLR, SII, SIRI, and WMR were found to be associated with carotid plaque formation. Among them, MLR had the strongest association with the incidence of carotid plaques (odd ratio[OR]:1.889; 95% confidence interval[CI]:1.406–2.539) and hyperechoic plaques (OR:2.024; 95% CI:1.481–2.767). When MLR was viewed as a categorical variable, the risk of carotid plaque formation in Q4 was 1.4 times higher than that in Q1. The relationship between MLR and carotid plaques in females (OR:2.250; 95% CI:1.458–3.473) was stronger than that in males (OR: 1.638; 95% CI:1.102–-2.436). The relationship between MLR and carotid plaques in patients younger than 65 years (OR:3.597; 95% CI:2.379–5.439) was stronger than that in those older than 65 years (OR:1.577; 95% CI:1.046–2.378).ConclusionLeukocyte-derived ratios were related to the incidence, number, and echo characteristics of carotid plaques. In particular, MLR, an inflammatory biomarker that encompasses innate and adaptive immunity, may be of great value in revealing the incidence and echo characteristics of plaques.

Enhancing neutralizing activity against influenza H1N1/PR8 by engineering a single-domain VL-M2 specific into a bivalent form.

Flu disease, with high mortality and morbidity, is caused by the influenza virus. Influenza infections are most effectively prevented through vaccination, but it requires annual reformulation due to the antigenic shift or drift of hemagglutinin and neuraminidase proteins. Increasing resistance to available anti-influenza drugs was also recently reported. The M2 surface protein of the influenza virus is an attractive target for universal vaccine development as it is highly conserved and multifunctional throughout the viral life cycle. This study aimed to discover a single-chain variable fragment (scFv) targeting the M2 protein of influenza A H1N1/PR8, showing neutralizing activity through plaque inhibition in virus replication. Several candidates were isolated using bio-panning, including scFv and single-domain VL target M2 protein, which was displayed on the yeast surface. The scFv/VL proteins were obtained with high yield and high purity through soluble expression in E. coli BL21 (DE3) pLysE strains. A single-domain VL-M2-specific antibody, NVLM10, exhibited the highest binding affinity to influenza virions and was engineered into a bivalent format (NVL2M10) to improve antigen binding. Both antibodies inhibited virus replication in a dose-dependent manner, determined using plaque reduction- and immunocytochemistry assays. Furthermore, bivalent anti-M2 single-domain VL antibodies significantly reduced the plaque number and viral HA protein intensity as well as viral genome (HA and NP) compared to the monovalent single-domain VL antibodies. This suggests that mono- or bivalent single-domain VL antibodies can exhibit neutralizing activity against influenza virus A, as determined through binding to virus particle activity.

Focal-type, but not Diffuse-type, Amyloid Beta Plaques are Correlated with Alzheimer’s Neuropathology, Cognitive Dysfunction, and Neuroinflammation in the Human Hippocampus

Amyloid beta (Aβ) plaques are one of the hallmarks of Alzheimer’s disease (AD). However, currently available anti-amyloid therapies fail to show effectiveness in the treatment of AD in humans. It has been found that there are different types of Aβ plaque (diffuse and focal types) in the postmortem human brain. In this study, we aimed to investigate the correlations among different types of Aβ plaque and AD-related neuropathological and cognitive changes based on a postmortem human brain bank in China. The results indicated that focal plaques, but not diffuse plaques, significantly increased with age in the human hippocampus. We also found that the number of focal plaques was positively correlated with the severity of AD-related neuropathological changes (measured by the “ABC” scoring system) and cognitive decline (measured by the Everyday Cognitive Insider Questionnaire). Furthermore, most of the focal plaques were co-localized with neuritic plaques (identified by Bielschowsky silver staining) and accompanied by microglial and other inflammatory cells. Our findings suggest the potential of using focal-type but not general Aβ plaques as biomarkers for the neuropathological evaluation of AD.

Features of non-stenotic carotid plaque on computed tomographic angiography in patients with embolic stroke of undetermined source.

PurposeEmbolic stroke of undetermined source (ESUS) is a subset of cryptogenic stroke constituting a large proportion of acute ischemic strokes. This study aimed to assess the features of non-stenotic carotid plaque (<50%) on computed tomographic angiography (CTA) and to evaluate the association between non-stenotic carotid plaque and ESUS.MethodsFrom January 1 to December 31, 2019, a total of 60 consecutive patients with primary unilateral ESUS and <50% carotid artery stenosis, as determined using screening ultrasonography, were hospitalized in the Department of Neurology of our hospital. All enrolled patients underwent CTA to determine the composition and morphological features of non-stenotic carotid plaques using consecutive sections in both carotid arteries. The features of these plaques with and without ipsilateral stroke in patients with ESUS were compared.ResultsSixty ESUS images were included in the study, with 85 plaques. Forty-five (52.9%) of these plaques were ipsilateral and 40 (47.1%) were contralateral to the stroke. Compared to that of the contralateral plaque group, the maximum carotid plaque thickness and plaque length of the ipsilateral group were greater (2.1 mm vs. 1.5 mm, p = 0.03; 20.8 mm vs. 12.1 mm, p = 0.02); however, there were no significant differences in the degree of luminal stenosis, presence of soft plaque and calcified plaque, and the number of ulcers on the plaque surface between the two groups. Similarly, the number of plaques with thickness >3 mm in the ipsilateral group was greater than in the contralateral group (30 vs. 13, p = 0.01). A lipid core was more common in individuals with ipsilateral strokes than in those with contralateral strokes (19 vs. 7, p = 0.02). Regression analysis showed that plaque lipid core area was an independent risk factor for ESUS (odds ratio, 1.92; 95% confidence interval, 1.22–3.04; p = 0.03).ConclusionsNon-stenotic carotid plaques could be an etiology of acute ischemic strokes classified as ESUS. The presence of a lipid core was a risk factor in individuals with non-stenotic carotid plaques.

Retinal Infarction: A Pilot Study on the Efficacy and Safety of Intravenous Thrombolysis and Underlying Aetiologies.

Background: Treatment of non-arteritic central retinal artery occlusion is still inconsistent. Therefore, the current study aimed to evaluate the efficacy of intravenous thrombolysis (IVT) and describe the prevalence of co-occurring ischemic brain lesions in patients with acute visual loss due to ischemia. Methods: We analysed 38 consecutive patients with acute visual loss between January 2015 and June 2020. Patients presenting within 4.5 h of symptom onset without any contraindication were treated with IVT. Patients underwent neurologic and ophthalmologic examination and diagnostic workup for the underlying aetiology. Follow-up was performed after 3 and 12 months. Results: Patients treated with IVT had a significantly better functional outcome at discharge compared to patients treated conservatively. No additional ischemic brain lesions were detected (0 of 38). Three patients had extracranial carotid artery stenosis ≥50%. Atrial fibrillation was present in four patients, three of whom already received oral anticoagulation. In the remaining 31 patients no embolic source was detected. However, the number of plaques were rated mild to moderate. Within three months, one patient developed transient visual loss while another suffered a contralateral transient ischemic attack. Conclusions: IVT may represent a safe and effective treatment option in patients with isolated visual loss due to ischemia. The aetiology was atherosclerotic burden rather than embolism caused by carotid stenosis or atrial fibrillation, bringing the current diagnostic procedure and therapy into question. Randomized trials are necessary to evaluate the efficacy and safety of IV thrombolysis and clarify the aetiology of isolated visual loss due to ischemia.

The age-specific pathological changes of β-amyloid plaques in the cortex and hippocampus of APP/PS1 transgenic AD mice

ABSTRACT Objective Numerous pathological variations and complex interactions are involved in the long period prior to cognitive decline in brains with Alzheimer’s disease (AD). Thus, elucidation of the pathological disorders can facilitate early AD diagnosis. The aim of this study was to investigate the age-specific pathological changes of β-amyloid plaques in brain tissues of AD mice at different ages. Methods We arranged the most widely available APP/PS1 transgenic AD models into six age groups: 3, 4 and 6 months (these three groups mimicked early-clinical stage AD), 9, 12 and 15 months (these three groups mimicked late-clinical stage AD). Cell morphology and arrangement in the cortex and hippocampus were observed by hematoxylin and eosin (HE) staining. Congo red staining and immunohistochemical staining were performed to exhibit the distribution of β-amyloid plaques in the cortex and hippocampus of AD brains. Results Our results found that as age increased, the nuclei of cortical and hippocampal cells in AD mice were severely damaged. The number and area of β-amyloid plaques increased in AD mice in correspondence with age revealed by histological experiments. Importantly, β-amyloid plaques were detected in the cortex and hippocampus of 6-month-old AD mice shown by Congo red staining while detected in the cortex and hippocampus of 4-month-old AD mice shown by immunohistochemical staining. Conclusions The current study revealed the age-related pathological changes of β-amyloid plaques in the cortex and hippocampus of AD mice and displayed a higher specificity of immunohistochemical staining than Congo red staining when detecting pathological changes of brain tissues.

Adult-Onset Deficiency of Mitochondrial Complex III in a Mouse Model of Alzheimer's Disease Decreases Amyloid Beta Plaque Formation.

For decades, mitochondrial dysfunctions and the generation of reactive oxygen species have been proposed to promote the development and progression of the amyloid pathology in Alzheimer's disease, but this association is still debated. It is unclear whether different mitochondrial dysfunctions, such as oxidative phosphorylation deficiency and oxidative stress, are triggers or rather consequences of the formation of amyloid aggregates. Likewise, the role of the different mitochondrial oxidative phosphorylation complexes in Alzheimer's patients' brain remains poorly understood. Previous studies showed that genetic ablation of oxidative phosphorylation enzymes from early age decreased amyloid pathology, which were unexpected results. To better model oxidative phosphorylation defects in aging, we induced the ablation of mitochondrial Complex III (CIIIKO) in forebrain neurons of adult mice with amyloid pathology. We found that mitochondrial Complex III dysfunction in adult neurons induced mild oxidative stress but did not increase amyloid beta accumulation. On the contrary, CIIIKO-AD mice showed decreased plaque number, decreased Aβ42 toxic fragment, and altered amyloid precursor protein clearance pathway. Our results support the hypothesis that mitochondrial dysfunctions alone, caused by oxidative phosphorylation deficiency, is not the cause of amyloid accumulation.

Evaluation of anti-parasitic activities of new quinolones containing nitrofuran moiety against Toxoplasma gondii

Toxoplasmosis is a disease with a worldwide prevalence that is caused by Toxoplasma gondii. Pyrimethamine and sulfadiazine are two pharmacological agents commonly used to treat of this infection. However, they are accompanied by some side effects. Therefore, the identifying of new drugs with low toxocytosis seems to be a matter of vital importance. Quinolones are DNA replication inhibitors, exerting inhibitory effects against many pathogens, including bacteria, mycoplasma, and protozoa. Given the importance of quinolones and their efficacy, the present in vitro study was conducted to investigate the antiparasitic activities of new quinolones (NFQ-2, NFQ-5, and NFQ-6) containing nitrofuran moiety against T. gondii. To this end, Vero cells were incubated with various concentrations of new quinolones and pyrimethamine (positive control) to determine their viability. Subsequently, they were infected with T. gondii (RH strain) and then subjected to drug treatment. The obtained IC50 values were 3.60, 4.84, 5.59, 3.44 and 2.75 μg/mL for NFQ-2, NFQ-5, NFQ-6, ciprofloxacin and pyrimethamine, respectively. The CC50 values for the NFQ-2, NFQ-5, and NFQ-6 were 25.20, 29.89, and 28.43 μg/mL, indicating the selectivity indexes more than 5 for these compounds. The anti-Toxoplasma efficiency was determined by evaluating infection index, number and size of plaques, and T. gondii intracellular proliferation. As the results indicated, the administration of new quinolone derivatives resulted in the reduction of intracellular proliferation, infection index, and the number and size of plaques in comparison to uninfected treated cells (P < 0.05). The results were indicative of a considerable synergetic effect when each of the derivatives was used in combination with pyrimethamine, compared to when used alone. Based on our results, the nitrofuran-derived quinolones can be considered as new leads for the design of new anti-Toxoplasma agents.

Features of global longitudinal deformation of the left ventricle in relation to coronary and carotid atherosclerosis in patients with coronary artery disease

Background and Aims : Identify the relationship of the LV deformation properties with the presence of coronary and carotid atherosclerosis in patients with CAD.Methods: 94 patients with CAD of class II-IV aged 40 to 70 years were studied by the general clinical and laboratory blood tests, Holter -ECG monitoring, TTE, 2D-Echo with speckle tracking (STE), ultrasound of carotid artery lesions and coronary angiography (CAG). The SYNTAX score was calculated retrospectively in accordance with the SYNTAX evaluation algorithm. All patients were divided into 2 groups: group 1 included patients with a low syntax index (0-22); group 2 included patients with an average syntax index (23-32). A more objective quantitative assessment of the contractile function of the LV myocardium was obtained by assessing the global longitudinal deformation (GLS) and the strain rate (SR).Results: A comparative analysis showed that in group 2, GLS and SR indicators were significantly lower than in group 1 (P=0.0001 and P=0.0133, respectively). GLS was significantly correlated with LVL (r=-0.309; P<0.005), with the degree of atherosclerotic damage to the coronary arteries (r=0.925; P<0.005) and the number of atherosclerotic plaques in the carotid arteries (r=0.245; P<0.05). SR was also correlated with LVL (r=-0.281; P<0.005), coronary artery disease (r=0.767; P<0.0005) and the number of atherosclerotic plaques of the carotid arteries (r=0.233; P<0.05).Conclusions: The results obtained indicate the diagnostic value of STE with the determination of GLS and SR in a comprehensive assessment of severity of coronary and carotid atherosclerosis within group of patients with CAD. Background and Aims : Identify the relationship of the LV deformation properties with the presence of coronary and carotid atherosclerosis in patients with CAD. Methods: 94 patients with CAD of class II-IV aged 40 to 70 years were studied by the general clinical and laboratory blood tests, Holter -ECG monitoring, TTE, 2D-Echo with speckle tracking (STE), ultrasound of carotid artery lesions and coronary angiography (CAG). The SYNTAX score was calculated retrospectively in accordance with the SYNTAX evaluation algorithm. All patients were divided into 2 groups: group 1 included patients with a low syntax index (0-22); group 2 included patients with an average syntax index (23-32). A more objective quantitative assessment of the contractile function of the LV myocardium was obtained by assessing the global longitudinal deformation (GLS) and the strain rate (SR). Results: A comparative analysis showed that in group 2, GLS and SR indicators were significantly lower than in group 1 (P=0.0001 and P=0.0133, respectively). GLS was significantly correlated with LVL (r=-0.309; P<0.005), with the degree of atherosclerotic damage to the coronary arteries (r=0.925; P<0.005) and the number of atherosclerotic plaques in the carotid arteries (r=0.245; P<0.05). SR was also correlated with LVL (r=-0.281; P<0.005), coronary artery disease (r=0.767; P<0.0005) and the number of atherosclerotic plaques of the carotid arteries (r=0.233; P<0.05). Conclusions: The results obtained indicate the diagnostic value of STE with the determination of GLS and SR in a comprehensive assessment of severity of coronary and carotid atherosclerosis within group of patients with CAD.

Clonal hematopoiesis are not associated with an increased systemic inflammation, ATHerosclerosis nor incidence of atherothrombosis: Results from the 3-city study (CHIP-3C)

Background and Aims : Clonal hematopoiesis of indeterminate Potential (CHIP) is defined by the detection of leukemia-associated mutations in the absence of hematological malignancy. This condition is associated with an increased mortality mainly driven by athero-thrombotic complications. Previous studies in mouse models demonstrated that CHIP increase atherosclerosis development. However the association between CHIP, atherosclerosis and athero-thrombosis remains poorly evaluated in patients.Methods: The 3-city study is a population-based longitudinal study that enrolled individuals aged ≥65 years. In this cohort, we selected 322 persons who had no cardiovascular event before inclusion. Eighty five of them suffered from a myocardial infarction or stroke during the 12-year follow-up. We searched for CHIP by a targeted NGS strategy on DNA collected at inclusion. Anthropomorphic, cardiovascular (risk factors, diet, atherosclerosis) and biological (CRP level) data at inclusion as well as incidence of athero-thrombotic events were compared between patients with or without CHIP.Results: A CHIP was detected in 41% of patients. As described, most patients presented mutations in DNMT3A (46%) and TET2 (30%). Patients with CHIP were slightly older than patients without CHIP (74.2 years VS 73 years, p=0.03). Neither the cardiovascular risk profile, nor the CRP levels (1.66 VS 1.75), nor the number of atheromatous plaques nor the intima-media thickness (0.67 VS 0.68) were different between patients with and without CHIP. The incidence of athero-thrombotic complications (myocardial infarction or stroke) was similar between patients with a CHIP and patients without.Conclusions: In conclusion, CHIP, in particular involving DNMT3A mutations, are not strongly associated with systemic inflammation, atherosclerosis or athero-thrombotic events. Background and Aims : Clonal hematopoiesis of indeterminate Potential (CHIP) is defined by the detection of leukemia-associated mutations in the absence of hematological malignancy. This condition is associated with an increased mortality mainly driven by athero-thrombotic complications. Previous studies in mouse models demonstrated that CHIP increase atherosclerosis development. However the association between CHIP, atherosclerosis and athero-thrombosis remains poorly evaluated in patients. Methods: The 3-city study is a population-based longitudinal study that enrolled individuals aged ≥65 years. In this cohort, we selected 322 persons who had no cardiovascular event before inclusion. Eighty five of them suffered from a myocardial infarction or stroke during the 12-year follow-up. We searched for CHIP by a targeted NGS strategy on DNA collected at inclusion. Anthropomorphic, cardiovascular (risk factors, diet, atherosclerosis) and biological (CRP level) data at inclusion as well as incidence of athero-thrombotic events were compared between patients with or without CHIP. Results: A CHIP was detected in 41% of patients. As described, most patients presented mutations in DNMT3A (46%) and TET2 (30%). Patients with CHIP were slightly older than patients without CHIP (74.2 years VS 73 years, p=0.03). Neither the cardiovascular risk profile, nor the CRP levels (1.66 VS 1.75), nor the number of atheromatous plaques nor the intima-media thickness (0.67 VS 0.68) were different between patients with and without CHIP. The incidence of athero-thrombotic complications (myocardial infarction or stroke) was similar between patients with a CHIP and patients without. Conclusions: In conclusion, CHIP, in particular involving DNMT3A mutations, are not strongly associated with systemic inflammation, atherosclerosis or athero-thrombotic events.

Monomeric form of C-reactive protein in the assessment of the residual inflammatory cardiovascular risk in patients with subclinical carotid atherosclerosis.

Aim To study the relationship between monomeric C-reactive protein (mCRP) and the progression of asymptomatic carotid atherosclerosis in patients with a moderate risk for cardiovascular diseases (CVD) as assessed with the SCORE model.Material and methods The study included 80 men and women aged 53.1±5.8 years assigned to the category of a moderate risk for CVDs by the SCORE model with a low-density lipoprotein cholesterol (LDL-C) level of 2.7-4.8 mmol/l and asymptomatic, hemodynamically insignificant (&lt;50% luminal narrowing) carotid atherosclerosis according to ultrasonic data. All patients were prescribed atorvastatin to achieve a LDL-C level &lt;2.6 mmol/l. After 7 years of follow-up, ultrasonic examination of carotid arteries was performed, and concentrations of high-sensitivity C-reactive protein (hsCRP) and mCRP were measured.Results A concentration of LDL-C &lt;2.6 mmol/l was achieved in all patients. The progression of atherosclerosis as determined by an increased number of atherosclerotic plaques (ASPs), was observed in 45 (56 %) patients. At 7 months of follow-up, concentrations of cCRP were higher in the group of patients with progressive carotid atherosclerosis, while the levels of hsCRP did not differ between the groups. Increased mCRP concentrations were associated with changes in variables of the "atherosclerotic load", including the number of ASPs, total ASP height, and the intima-media thickness (IMT). In patients with a median mCRP concentration of 5.2 [3.3; 7.1] µg/l and more, the increases in mean ACP number and total ASP height were considerably higher than in patients with mCRP concentrations lower than the median (3.9 and 2.7 times, respectively), whereas the odds ratio for the progression of asymptomatic carotid atherosclerosis was 5.5 (95 % confidence interval, CI: 2.1-14.6; p=0.001). ROC analysis showed that the concentration of hsCRP had no predictive value for prognosis of asymptomatic carotid atherosclerosis (p=0.16), while the area under the ROC curve (AUC) for mCRP was 0.75±0.056 (95 % CI: 0.64-0.86; p=0.001).Conclusion According to the results of 7-year follow-up, the plasma concentration of mCRP was significantly higher in patients with an increased number of ASPs than in patients without this increase. An increased level of mCRP may indicate a higher inflammatory risk of CVD.

The monomeric C-reactive protein level is associated with the increase in carotid plaque number in patients with subclinical carotid atherosclerosis.

The high-sensitivity C-reactive protein (hsCRP) assay measures the level of the pentameric form of CRP in blood. Currently, there are no available assays measuring the level of the monomeric form of CRP (mCRP), produced at sites of local inflammation. We developed an assay measuring the mCRP level in blood plasma with functional beads for flow cytometry. The assay was used to measure the mCRP level in 80 middle-aged individuals with initially moderate cardiovascular SCORE risk. By the time of the mCRP measurement, the patients have been followed up for subclinical carotid atherosclerosis progression for 7 years. Ultrasound markers of subclinical atherosclerosis, which included plaque number (PN) and total plaque height (PH), were measured at baseline and at the 7th-year follow-up survey. Inflammatory biomarkers, including mCRP, hsCRP, inteleukin-6 (IL-6) and von Willebrand factor (VWF) level, were measured at the 7th-year follow-up survey. The median level of mCRP was 5.2 (3.3; 7.1) μg/L, hsCRP 1.05 (0.7; 2.1) mg/L, IL-6 0.0 (0.0; 2.8) pg/mL, VWF 106 (77; 151) IU/dL. In the patients with the mCRP level below median vs. the patients with the median mCRP level or higher, change from baseline in PN was 0.0 (0.0; 1.0) vs. 1.0 (1.0; 2.0) and PH 0.22 (−0.24; 1.91) mm vs. 1.97 (1.14; 3.14) mm, respectively (p < 0.05). The adjusted odds ratio for the formation of new carotid atherosclerotic plaques was 4.7 (95% CI 1.7; 13.2) for the patients with the median mCRP level or higher. The higher mCRP level is associated with the more pronounced increase in PN and PH in patients with normal level of traditional inflammatory biomarkers and initially moderate cardiovascular SCORE risk.

NMDA receptor antagonists reduce amyloid-β deposition by modulating calpain-1 signaling and autophagy, rescuing cognitive impairment in 5XFAD mice

Overstimulation of N-methyl-d-aspartate receptors (NMDARs) is the leading cause of brain excitotoxicity and often contributes to neurodegenerative diseases such as Alzheimer’s Disease (AD), the most common form of dementia. This study aimed to evaluate a new NMDA receptor antagonist (UB-ALT-EV) and memantine in 6-month-old female 5XFAD mice that were exposed orally to a chronic low-dose treatment. Behavioral and cognitive tests confirmed better cognitive performance in both treated groups. Calcium-dependent protein calpain-1 reduction was found after UB-ALT-EV treatment but not after memantine. Changes in spectrin breakdown products (SBDP) and the p25/p35 ratio confirmed diminished calpain-1 activity. Amyloid β (Aβ) production and deposition was evaluated in 5XFAD mice and demonstrated a robust effect of NMDAR antagonists on reducing Aβ deposition and the number and size of Thioflavin-S positive plaques. Furthermore, glycogen synthase kinase 3β (GSK3β) active form and phosphorylated tau (AT8) levels were diminished after UB-ALT-EV treatment, revealing tau pathology improvement. Because calpain-1 is involved in autophagy activation, autophagic proteins were studied. Strikingly, results showed changes in the protein levels of unc-51-like kinase (ULK-1), beclin-1, microtubule-associated protein 1A/1B-light chain 3(LC3B-II)/LC3B-I ratio, and lysosomal-associated membrane protein 1 (LAMP-1) after NMDAR antagonist treatments, suggesting an accumulation of autophagolysosomes in 5XFAD mice, reversed by UB-ALT-EV. Likewise, treatment with UB-ALT-EV recovered a WT mice profile in apoptosis markers Bcl-2, Bax, and caspase-3. In conclusion, our results revealed the potential neuroprotective effect of UB-ALT-EV by attenuating NMDA-mediated apoptosis and reducing Aβ deposition and deposition jointly with the autophagy rescue to finally reduce cognitive alterations in a mice model of familial AD.

Construction of BHV-1 UL41 Defective Virus Using the CRISPR/Cas9 System and Analysis of Viral Replication Properties.

Bovine herpesvirus type 1 (BHV-1) is a neurotropic herpesvirus that causes infectious rhinotracheitis and vulvovaginitis in cattle. The virion host shutoff protein encoded by the BHV-1 UL41 gene is highly conserved in the Alphaherpesvirinae subfamily. This protein can degrade viral and host messenger RNA (mRNA) to interrupt host defense and facilitate the rapid proliferation of BHV-1. However, studies on the BHV-1 UL41 gene are limited, and BHV-1 defective virus construction using the CRISPR/Cas9 system is somewhat challenging. In this study, we rapidly constructed a BHV-1 UL41-deficient strain using the CRISPR/Cas9 system in BL primary bovine-derived cells. BHV-1 UL41-defective mutants were screened by Western blot analysis using specific polyclonal antibodies as the primary antibodies. During the isolation and purification of the defective strain, a mixed virus pool edited by an efficient single-guide RNA (sgRNA) showed a plaque number reduction. Viral growth property assessment showed that BHV-1 UL41 was dispensable for replication, but the UL41-defective strain exhibited early and slowed viral replication. Furthermore, the BHV-1 UL41-deficient strain exhibited enhanced sensitivity to temperature and acidic environments. The BHV-1 UL41-deficient strain regulated viral and host mRNA levels to affect viral replication.

Quantitative plaque analysis with A.I.-augmented CCTA in end-stage renal disease and complex CAD

BackgroundAdverse cardiovascular events are a significant cause of mortality in end-stage renal disease (ESRD) patients. High-risk plaque anatomy may be a significant contributor. However, their atherosclerotic phenotypes have not been described. We sought to define atherosclerotic plaque characteristics (APC) in dialysis patients using artificial-intelligence augmented CCTA. MethodsWe retrospectively analyzed ESRD patients referred for CCTA using an FDA approved artificial-intelligence augmented-CCTA program (Cleerly). Coronary lesions were evaluated for APCs by CCTA. APCs included percent atheroma volume(PAV), low-density non-calcified-plaque (LD-NCP), non-calcified-plaque (NCP), calcified-plaque (CP), length, and high-risk-plaque (HRP), defined by LD-NCP and positive arterial remodeling >1.10 (PR). Results79 ESRD patients were enrolled, mean age 65.3 years, 32.9% female. Disease distribution was non-obstructive (65.8%), 1-vessel disease (21.5%), 2-vessel disease (7.6%), and 3-vessel disease (5.1%). Mean total plaque volume (TPV) was 810.0 mm3, LD-NCP 16.8 mm3, NCP 403.1 mm3, and CP 390.1 mm3. HRP was present in 81.0% patients. Patients with at least one >50% stenosis, or obstructive lesions, had significantly higher TPV, LD-NCP, NCP, and CP. Patients >65 years had more CP and higher PAV. ConclusionOur study provides novel insight into ESRD plaque phenotypes and demonstrates that artificial-intelligence augmented CCTA analysis is feasible for CAD characterization despite severe calcification. We demonstrate elevated plaque burden and stenosis caused by predominantly non-calcified-plaque. Furthermore, the quantity of calcified-plaques increased with age, with men exhibiting increased number of 2-feature plaques and higher plaque volumes. Artificial-intelligence augmented CCTA analysis of APCs may be a promising metric for cardiac risk stratification and warrants further prospective investigation.

Colchicine Impacts Leukocyte Trafficking in Atherosclerosis and Reduces Vascular Inflammation.

BackgroundInflammation strongly contributes to atherosclerosis initiation and progression. Consequently, recent clinical trials pharmacologically targeted vascular inflammation to decrease the incidence of atherosclerosis-related complications. Colchicine, a microtubule inhibitor with anti-inflammatory properties, reduced cardiovascular events in patients with recent acute coronary syndrome and chronic coronary disease. However, the biological basis of these observations remains elusive. We sought to explore the mechanism by which colchicine beneficially alters the course of atherosclerosis.Methods and ResultsIn mice with early atherosclerosis (Apoe-/- mice on a high cholesterol diet for 8 weeks), we found that colchicine treatment (0.25 mg/kg bodyweight once daily over four weeks) reduced numbers of neutrophils, inflammatory monocytes and macrophages inside atherosclerotic aortas using flow cytometry and immunohistochemistry. Consequently, colchicine treatment resulted in a less inflammatory plaque composition and reduced plaque size. We next investigated how colchicine prevented plaque leukocyte expansion and found that colchicine treatment mitigated recruitment of blood neutrophils and inflammatory monocytes to plaques as revealed by adoptive transfer experiments. Causally, we found that colchicine reduced levels of both leukocyte adhesion molecules and receptors for leukocyte chemoattractants on blood neutrophils and monocytes. Further experiments showed that colchicine treatment reduced vascular inflammation also in post-myocardial infarction accelerated atherosclerosis through similar mechanisms as documented in early atherosclerosis. When we examined whether colchicine also decreased numbers of macrophages inside atherosclerotic plaques by impacting monocyte/macrophage transitioning or in-situ proliferation of macrophages, we report that colchicine treatment did not influence macrophage precursor differentiation or macrophage proliferation using cell culture experiments with bone marrow derived macrophages.ConclusionsOur data reveal that colchicine prevents expansion of plaque inflammatory leukocytes through lowering recruitment of blood myeloid cells to plaques. These data provide novel mechanistic clues on the beneficial effects of colchicine in the treatment of atherosclerosis and may inform future anti-inflammatory interventions in patients at risk.

Four-repeat tauopathies and late-onset psychiatric disorders: Etiological relevance or incidental findings?

Argyrophilic grain disease (AGD), progressive supranuclear palsy (PSP) and corticobasal degeneration are four-repeat (4R) tauopathies that develop in the presenium or later. Whether these diseases are associated with the occurrence of late-onset psychiatric disorders remains unclear. To facilitate the accumulation of clinicopathological findings regarding this issue, we here present a selected series of 11 cases that clinically developed psychotic disorder (n=7; age at onset: 41-75 years), depressive disorder (n=1; 49 years), bipolar disorder (n=2; 32 and 37 years) and somatoform disorder (n=1; 88 years), and had at least one pathological hallmark of these tauopathies. The mean age at death was 74.3 years. No case showed dementia, at least in the early stage of the course. Nine cases had AGD. Granular fuzzy astrocytes in the amygdala were noted in all AGD cases and one non-AGD case. Two AGD cases had tufted astrocytes (TAs) in the amygdala but not in the frontal cortex and striatum. Three AGD and two non-AGD cases had TAs in the frontal cortex and/or striatum but not in the amygdala. One AGD case had a small number of astrocytic plaques in the frontal cortex, striatum and globus pallidus. Only one case was diagnosed as atypical PSP according to the NINDS-PSP neuropathological criteria. No case had high-level Alzheimer's disease pathology, Lewy body disease or limbic-predominant age-related TDP-43 encephalopathy. Two cases had mild neuronal loss in the hippocampus and substantia nigra, respectively. Clinicopathological studies focusing especially on early changes of 4R tauopathies, as well as the development of surrogate markers of these diseases, may be necessary for better understanding of the pathogenic backgrounds of late-onset psychiatric disorders.

Passive immunization against COVID-19 by anti-SARS-CoV-2 spike IgG in commercially available immunoglobulin preparations in severe antibody deficiency

Passive immunization against COVID-19 by anti-SARS-CoV-2 spike IgG in commercially available immunoglobulin preparations in severe antibody deficiency