Predicting Acute Cardiovascular Complications in COVID-19: Insights from a Specialized Cardiac Referral Department.

BACKGROUND COVID-19 increases the risk of acute cardiovascular diseases (CVDs), including acute coronary syndrome (ACS), acute pulmonary embolism (APE), and acute myocarditis (AMyo). The actual impact of CVDs on mortality of patients with COVID-19 remains unknown. This study aimed to determine whether CVDs influence the course of COVID-19 pneumonia and if they can be easily detected by using common tests and examinations. MATERIAL AND METHODS Data of 249 consecutive patients with COVID-19 hospitalized in a dedicated cardiology department were analyzed. On admission, clinical status, biomarkers, computed tomography, and bedside echocardiography were performed. RESULTS D-dimer level predicted APE (AUC=0.850 95% CI [0.765; 0.935], P<0.001) with sensitivity of 69.4% and specificity of 96.2% for a level of 4968.0 ng/mL, and NT-proBNP predicted AMyo (AUC=0.692 95% CI [0.502; 0.883], P=0.004) and showed sensitivity of 54.5%, with specificity of 86.5% for the cut-off point of 8970 pg/mL. Troponin T levels were not useful for diagnostic differentiation between CVDs. An extent of lung involvement predicted mortality (OR=1.03 95% CI [1.01;1.04] for 1% increase, P<0.001). After adjusting for lung involvement, ACS increased mortality, compared with COVID-19 pneumonia only (OR=5.27 95% CI [1.76; 16.38] P=0.003), while APE and AMyo did not affect risk for death. CONCLUSIONS D-dimer and NT-proBNP, but not troponin T, are useful in differentiating CVDs in patients with COVID-19. ACS with COVID-19 increased in-hospital mortality independently from extent of lung involvement, while coexisting APE or AMyo did not.

Role of NT-proBNP and lung ultrasound in diagnosing and classifying heart failure in a hospitalized oldest-old population: a cross-sectional study.

AIM: Diagnosing and classifying heart failure (HF) in the oldest-old patients has technical and interpretation issues, especially in the acute setting. We assessed the usefulness of both N-terminal pro-brain natriuretic peptide (NT-proBNP) and lung ultrasound (LUS) for confirming HF diagnosis and predicting, among hospitalized HF patients, those with reduced ejection fraction (HFrEF). METHODS: We performed a cross-sectional study on 148 consecutive patients aged ≥ 80 years admitted to our Internal Medicine and Geriatrics ward with at least one symptom/sign compatible with HF and NT-proBNP ≥ 125 pg/mL. We measured serum NT-proBNP levels and performed LUS and transthoracic echocardiography (TTE) on admission before diuretic therapy. We divided our cohort into three subgroups according to the left ventricular ejection fraction (LVEF): reduced (LVEF ≤ 40%), mildly-reduced (LVEF = 41-49%) and preserved (LVEF ≥ 50%). RESULTS: The mean age was 88±5 years. Male prevalence was 42%. Patients with HFrEF were 19%. Clinical features and laboratory parameters did not differ between the three subgroups, except for higher NT-proBNP in HFrEF patients, which also had a higher number of total B-lines and intercostal spaces of pleural effusion at LUS. Overall, NT-proBNP showed an inverse correlation with LVEF (r = -0.22, p = 0.007) and a direct correlation with age, total pulmonary B-lines, and intercostal spaces of pleural effusion. According to the ROCs, NT-proBNP levels, pulmonary B-lines and pleural effusion extension were poorly predictive for HFrEF. The best-performing cut-offs were 9531 pg/mL for NT-proBNP (SP 0.70, SE 0.50), 13 for total B-lines (SP 0.69, SE 0.85) and one intercostal space for pleural effusion (SP 0.55, SE 0.89). Patients with admission NT-proBNP ≥ 9531 pg/mL had a 2-fold higher risk for HFrEF (OR 2.5, 95% CI 1.3-4.9), while we did not find any association for total B-lines ≥ 13 or pleural effusion ≥ 1 intercostal space with HFrEF. A significant association with HFrEF emerged for the combination of NT-proBNP ≥ 9531 pg/mL, total B-lines ≥ 13 and intercostal spaces of pleural effusion ≥ 1 (adjusted OR 4.3, 95% CI 1.5-12.9). CONCLUSIONS: Although NT-proBNP and LUS help diagnose HF, their accuracy in discriminating HFrEF from non-HFrEF was poor in our real-life clinical study on oldest-old hospitalized patients, making the use of TTE still necessary to distinguish HF phenotypes in this peculiar setting. These data require confirmation in more extensive and longer prospective studies.

Application of fiber loop ringdown spectroscopy technique for a new approach to beta-amyloid monitoring for Alzheimer Disease's early detection.

A novel fiber optic biosensor was purposed for a new approach to monitor amyloid beta protein fragment 1-42 (Aß42) for Alzheimer's Disease (AD) early detection. The sensor was fabricated by etching a part of fiber from single mode fiber loop in pure hydrofluoric acid solution and utilized as a Local Optical Refractometer (LOR) to monitor the change Aß42 concentration in Artificial Cerebrospinal Fluid (ACSF). The Fiber Loop Ringdown Spectroscopy (FLRDS) technique is an ultra-sensitive measurement technique with low-cost, high sensitivity, real-time measurement, continuous measurement and portability features that was utilized with a fiber optic sensor for the first time for the detection of a biological signature in an ACSF environment. Here, the measurement is based on the total optical loss detection when specially fabricated sensor heads were immersed into ACSF solutions with and without different concentrations of Aß42 biomarkers since the bulk refractive index change was performed. Baseline stability and the reference ring down times of the sensor head were measured in the air as 0.87% and 441.6µs ± 3.9µs, respectively. Afterward, the total optical loss of the system was measured when the sensor head was immersed in deionized water, ACSF solution, and ACSF solutions with Aß42 in different concentrations. The lowest Aß42 concentration of 2 ppm was detected by LOR. Results showed that LOR fabricated by single-mode fibers for FLRDS system design are promising candidates to be utilized as fiber optic biosensors after sensor head modification and have a high potential for early detection applications of not only AD but possibly also several fatal diseases such as diabetes and cancer.

Risk stratification and prognosis prediction using cardiac biomarkers in COVID-19: a single-centre retrospective cohort study.

OBJECTIVE: There is a need for a robust tool to stratify the patient's risk with COVID-19. We assessed the prognostic values of cardiac biomarkers for COVID-19 patients. METHODS: This is a single-centre retrospective cohort study. Consecutive laboratory-confirmed COVID-19 patients admitted to the Kobe City Medical Center General Hospital from July 2020 to September 2021 were included. We obtained cardiac biomarker values from electronic health records and institutional blood banks. We stratified patients with cardiac biomarkers as high-sensitive troponin I (hsTnI), N-terminal pro-B-type natriuretic peptide (NT-proBNP), creatine kinase (CK) and CK myocardial band (CK-MB), using the clinically relevant thresholds. Prespecified primary outcome measure was all-cause death. RESULTS: A total of 917 patients were included. hsTnI, NT-proBNP, CK and CK-MB were associated with the significantly higher cumulative 30-day incidence of all-cause death (hsTnI: <5.0 ng/L group; 4.3%, 5.0 ng/L-99%ile upper reference limit (URL) group; 8.8% and ≥99% ile URL group; 25.2%, p<0.001. NT-proBNP: <125 pg/mL group; 5.3%, 125-900 pg/mL group; 10.5% and ≥900 pg/mL group; 31.9%, p<0.001. CK:

Molecular dynamics simulations suggest the potential toxicity of fluorinated graphene to HP35 protein via unfolding the α-helix structure.

Fluorinated graphene, a two-dimensional nanomaterial composed of three atomic layers, a central carbon layer sandwiched between two layers of fluorine atoms, has attracted considerable attention across various fields, particularly for its potential use in biomedical applications. Nonetheless, scant effort has been devoted to assessing the potential toxicological implications of this nanomaterial. In this study, we scrutinize the potential impact of fluorinated graphene on a protein model, HP35 by utilizing extensive molecular dynamics (MD) simulation methods. Our MD results elucidate that upon adsorption to the nanomaterial, HP35 undergoes a denaturation process initiated by the unraveling of the second helix of the protein and the loss of the proteins hydrophobic core. In detail, substantial alterations in various structural features of HP35 ensue, including alterations in hydrogen bonding, Q value, and RMSD. Subsequent analyses underscore that hydrophobic and van der Waals interactions (predominant), alongside electrostatic energy (subordinate), exert influence over the adsorption of HP35 on the fluorinated graphene surface. Mechanistic scrutiny attests that the unrestrained lateral mobility of HP35 on the fluorinated graphene nanomaterial primarily causes the exposure of HP35's hydrophobic core, resulting in the eventual structural denaturation of HP35. A trend in the features of 2D nanostructures is proposed that may facilitate the denaturation process. Our findings not only substantiate the potential toxicity of fluorinated graphene but also unveil the underlying molecular mechanism, which thereby holds significance for the prospective utilization of such nanomaterials in the field of biomedicine.

Detection of NT-proBNP Using Optical Fiber Back-Reflection Plasmonic Biosensors.

Heart failure (HF) is a clinical entity included in cardiovascular diseases affecting millions of people worldwide, being a leading cause of hospitalization of older adults, and therefore imposing a substantial economic burden on healthcare systems. HF is characterized by dyspnea, fatigue, and edema associated with elevated blood levels of natriuretic peptides, such as N Terminal pro-B-type Natriuretic Peptide (NT-proBNP), for which there is a high demand for point of care testing (POCT) devices. Optical fiber (OF) biosensors offer a promising solution, capable of real-time detection, quantification, and monitoring of NT-proBNP concentrations in serum, saliva, or urine. In this study, immunosensors based on plasmonic uncladded OF tips were developed using OF with different core diameters (200 and 600 µm). The tips were characterized to bulk refractive index (RI), anddetection tests were conducted with NT-proBNP concentrations varying from 0.01 to 100 ng/mL. The 200 µm sensors showed an average total variation of 3.6 ± 2.5 mRIU, an average sensitivity of 50.5 mRIU/ng·mL-1, and a limit of detection (LOD) of 0.15 ng/mL, while the 600 µm sensors had a response of 6.1 ± 4.2 mRIU, a sensitivity of 102.8 mRIU/ng·mL-1, and an LOD of 0.11 ng/mL. Control tests were performed using interferents such as uric acid, glucose, and creatinine. The results show the potential of these sensors for their use in biological fluids.

CSF biomarkers of immune activation and Alzheimer's disease for predicting cognitive impairment risk in the elderly.

The immune system substantially influences age-related cognitive decline and Alzheimer's disease (AD) progression, affected by genetic and environmental factors. In a Mayo Clinic Study of Aging cohort, we examined how risk factors like APOE genotype, age, and sex affect inflammatory molecules and AD biomarkers in cerebrospinal fluid (CSF). Among cognitively unimpaired individuals over 65 (N = 298), we measured 365 CSF inflammatory molecules, finding age, sex, and diabetes status predominantly influencing their levels. We observed age-related correlations with AD biomarkers such as total tau, phosphorylated tau-181, neurofilament light chain (NfL), and YKL40. APOE4 was associated with lower Aß42 and higher SNAP25 in CSF. We explored baseline variables predicting cognitive decline risk, finding age, CSF Aß42, NfL, and REG4 to be independently correlated. Subjects with older age, lower Aß42, higher NfL, and higher REG4 at baseline had increased cognitive impairment risk during follow-up. This suggests that assessing CSF inflammatory molecules and AD biomarkers could predict cognitive impairment risk in the elderly.

[Mechanism of astragaloside â £ combined with Panax notoginseng saponins in regulating angiogenesis to treat cerebral ischemia based on network pharmacology and experimental verification].

Network pharmacology and animal and cell experiments were employed to explore the mechanism of astragaloside Ⅳ(AST Ⅳ) combined with Panax notoginseng saponins(PNS) in regulating angiogenesis to treat cerebral ischemia. The method of network pharmacology was used to predict the possible mechanisms of AST Ⅳ and PNS in treating cerebral ischemia by mediating angiogenesis. In vivo experiment: SD rats were randomized into sham, model, and AST Ⅳ(10 mg·kg~(-1)) + PNS(25 mg·kg~(-1)) groups, and the model of cerebral ischemia was established with middle cerebral artery occlusion(MCAO) method. AST Ⅳ and PNS were administered by gavage twice a day. the Longa method was employed to measure the neurological deficits. The brain tissue was stained with hematoxylin-eosin(HE) to reveal the pathological damage. Immunohistochemical assay was employed to measure the expression of von Willebrand factor(vWF), and immunofluorescence assay to measure the expression of vascular endothelial growth factor A(VEGFA). Western blot was employed to determine the protein levels of vascular endothelial growth factor receptor 2(VEGFR2), VEGFA, phosphorylated phosphatidylinositol 3-kinase(p-PI3K), and phosphorylated protein kinase B(p-AKT) in the brain tissue. In vitro experiment: the primary generation of rat brain microvascular endothelial cells(rBEMCs) was cultured and identified. The third-generation rBMECs were assigned into control, model, AST Ⅳ(50 µmol·L~(-1)) + PNS(30 µmol·L~(-1)), LY294002(PI3K/AKT signaling pathway inhibitor), 740Y-P(PI3K/AKT signaling pathway agonist), AST Ⅳ + PNS + LY294002, and AST Ⅳ + PNS + 740Y-P groups. Oxygen glucose deprivation/re-oxygenation(OGD/R) was employed to establish the cell model of cerebral ischemia-reperfusion injury. The cell counting kit-8(CCK-8) and scratch assay were employed to examine the survival and migration of rBEMCs, respectively. Matrigel was used to evaluate the tube formation from rBEMCs. The Transwell assay was employed to examine endothelial cell permeability. Western blot was employed to determine the expression of VEGFR2, VEGFA, p-PI3K, and p-AKT in rBEMCs. The results of network pharmacology analysis showed that AST Ⅳ and PNS regulated 21 targets including VEGFA and AKT1 of angiogenesis in cerebral infarction. Most of these 21 targets were involved in the PI3K/AKT signaling pathway. The in vivo experiments showed that compared with the model group, AST Ⅳ + PNS reduced the neurological deficit score(P<0.05) and the cell damage rate in the brain tissue(P<0.05), promoted the expression of vWF and VEGFA(P<0.01) and angiogenesis, and up-regulated the expression of proteins in the PI3K/AKT pathway(P<0.05, P<0.01). The in vitro experiments showed that compared with the model group, the AST Ⅳ + PNS, 740Y-P, AST Ⅳ + PNS + LY294002, and AST Ⅳ + PNS + 740Y-P improved the survival of rBEMCs after OGD/R, enhanced the migration of rBEMCs, increased the tubes formed by rBEMCs, up-regulated the expression of proteins in the PI3K/AKT pathway, and reduced endothelial cell permeability(P<0.05, P<0.01). Compared with the LY294002 group, the AST Ⅳ + PNS + LY294002 group showed increased survival rate, migration rate, and number of tubes, up-regulated expression of proteins in the PI3K/AKT pathway, and decreased endothelial cell permeability(P<0.05,P<0.01). Compared with the AST Ⅳ + PNS and 740Y-P groups, the AST Ⅳ + PNS + 740Y-P group presented increased survival rate, migration rate, and number of tubes and up-regulated expression of proteins in the PI3K/AKT pathway, and reduced endothelial cell permeability(P<0.01). This study indicates that AST Ⅳ and PNS can promote angiogenesis after cerebral ischemia by activating the PI3K/AKT signaling pathway.

[Expression relationship and significance of NEAT1 and miR-27a-3p in serum and cerebrospinal fluid of patients with Alzheimer disease].

OBJECTIVE: To explore the expression relationship and significance of long chain non-coding RNA nuclear-enriched abundant transcript 1 (LncRNA NEAT1) and miR-27a-3p in serum and cerebrospinal fluid of patients with Alzheimer disease (AD). METHODS: Sixty-six AD patients received by the department of neurology of our hospital from October 2019 to September 2021 were gathered, according to the clinical dementia rating scale score, they were grouped into mild group (≤1 point, n=41) and moderate-to-severe group (>1 point, n=25). Another 66 cases of serum and cerebrospinal fluid samples from outpatient physical examination personnel were regarded as the control group. The general information on all subjects was recorded and cognition was assessed; real-time quantitative PCR was performed to measure the expression levels of miR-27a-3p and NEAT1 in serum and cerebrospinal fluid; enzyme-linked immunosorbent assay was performed to measure the protein levels of ß-amyloid precursor protein cleaving enzyme 1 (BACE1), ß-amyloid (Aß) 40 and Aß42 in cerebrospinal fluid; Spearman' s method was performed to analyze the correlation of serum miR-27a-3p and NEAT1 levels with mini-mental state examination (MMSE) and montreal cognitive assessment (MoCA) scores; Pearson method was performed to analyze the correlation between serum miR-27a-3p and NEAT1 levels and Aß deposition standard uptake value ratio (SUVR) and cerebrospinal fluid miR-27a-3p, NEAT1, BACE1, Aß42 and Aß40 levels. RESULTS: The MMSE score [21 (17, 25), 9(7, 11) vs. 27 (21, 34)], MoCA score [17 (12, 21), 10 (7, 13) vs. 27 (21, 31)], serum miR-27a-3p level (0.55±0.13, 0.46±0.06 vs. 0.97±0.22), cerebrospinal fluid miR-27a-3p (0.48±0.10, 0.35±0.10 vs. 1.03±0.31), Aß42 levels [(303.55±36.77) ng/L, (231.45±34.14) ng/L vs. (499.99±53.63) ng/L] and Aß42/Aß40 ratio (0.030±0.008, 0.022±0.007 vs. 0.048±0.010) of AD patients in mild group and moderate-to-severe group were all lower than those in the control group, and the moderate-to-severe group were lower than the mild group (all P < 0.05); the serum NEAT1 level (2.31±0.64, 3.13±0.76 vs. 1.05±0.20), SUVR (1.50±0.29, 1.76±0.52 vs. 0.74±0.15), and cerebrospinal fluid NEAT1 (3.51±1.24, 4.30±1.65 vs. 1.01±0.23) and BACE1 levels [(55.78±5.98) µg/L, (72.32±16.08) µg/L vs. (21.39±3.73) µg/L] were higher than those in the control group, and the moderate-to-severe group were higher than the mild group (all P < 0.05). Serum NEAT1 level in AD patients was positively correlated with SUVR, cerebrospinal fluid NEAT1 and BACE1 (r=0.350, 0.606, 0.341, P < 0.05), and negatively correlated with MMSE score and MoCA score (r=-0.473, -0.482, all P < 0.05); serum miR-27a-3p level was positively correlated with cerebrospinal fluid miR-27a-3p level, MMSE score and MoCA score (r=0.695, 0.424, 0.412, all P < 0.05), and negatively correlated with SUVR and cerebrospinal fluid BACE1 level (r=-0.521, -0.447, all P < 0.05). CONCLUSION: The expression trends of NEAT1 and miR-27a-3p in the serum and cerebrospinal fluid of AD patients are consistent, the level of NEAT1 is increased, and the level of miR-27a-3p is decreased. The levels of the two are negatively correlated, which is related to the degree of Aß deposition in the brain of AD patients and is involved in the progression of AD.

How ATP suppresses the fibrillation of amyloid peptides: analysis of the free-energy contributions.

Recent experiments have revealed that adenosine triphosphate (ATP) suppresses the fibrillation of amyloid peptides - a process closely linked to neurodegenerative diseases such as Alzheimer's and Parkinson's. Apart from the adsorption of ATP onto amyloid peptides, the molecular understanding is still limited, leaving the underlying mechanism for the fibrillation suppression by ATP largely unclear, especially in regards to the molecular energetics. Here we provide an explanation at the molecular scale by quantifying the free energies using all-atom molecular dynamics simulations. We found that the changes of the free energies due to the addition of ATP lead to a significant equilibrium shift towards monomeric peptides in agreement with experiments. Despite ATP being a highly charged species, the decomposition of the free energies reveals that the van der Waals interactions with the peptide are decisive in determining the relative stabilization of the monomeric state. While the phosphate moiety exhibits strong electrostatic interactions, the compensation by the water solvent results in a minor, overall Coulomb contribution. Our quantitative analysis of the free energies identifies which intermolecular interactions are responsible for the suppression of the amyloid fibril formation by ATP and offers a promising method to analyze the roles of similarly complex cosolvents in aggregation processes.

Effect of total flavonoids of Dracocephalum moldavica L. On neuroinflammation in Alzheimer's disease model amyloid-ß (Aß1-42)-peptide-induced astrocyte activation.

One of the main pathological features noted in Alzheimer's disease (AD) is the presence of plagues of aggregated ß-amyloid (Aß1-42)-peptides. Excess deposition of amyloid-ß oligomers (AßO) are known to promote neuroinflammation. Sequentially, following neuroinflammation astrocytes become activated with cellular characteristics to initiate activated astrocytes. The purpose of this study was to determine whether total flavonoids derived from Dracocephalum moldavica L. (TFDM) inhibited Aß1-42-induced damage attributed to activated C8-D1A astrocytes. Western blotting and ELISA were used to determine the expression of glial fibrillary acidic protein (GFAP), and complement C3 to establish the activation status of astrocytes following induction from exposure to Aß1-42. Data demonstrated that stimulation of C8-D1A astrocytes by treatment with 40 µM Aß1-42 for 24 hr produced significant elevation in protein expression and protein levels of acidic protein (GFAP) and complement C3 accompanied by increased expression and levels of inflammatory cytokines. Treatment with TFDM or the clinically employed drug donepezil in AD therapy reduced production of inflammatory cytokines, and toxicity initiated following activation of C8-D1A astrocytes following exposure to Aß1-42. Therefore, TFDM similar to donepezil inhibited inflammatory secretion in reactive astrocytes, suggesting that TFDM may be considered as a potential compound to be utilized in AD therapy.

Characteristics and Prognosis of Type 2 Myocardial Infarction Through Worsening Renal Function and NT-proBNP in Older Adults with Pneumonia.

Background: Type 2 myocardial infarction (MI) is becoming more recognized. This study aimed to assess the factors linked to type 2 MI in older adults with pneumonia and further determine the predictive factors of 90-day adverse events (refractory heart failure, cardiogenic shock, and all-cause mortality). Methods: A single-center retrospective analysis was conducted among older adults with pneumonia. The primary outcome was the prevalence of type 2 MI. The secondary objective was to assess the adverse events in these patients with type 2 MI within 90 days. Results: A total of 2618 patients were included. Of these, 361 patients (13.8%) suffered from type 2 MI. Multivariable predictors of type 2 MI were chronic kidney disease (CKD), age-adjusted Charlson comorbidity index (ACCI) score, and NT-proBNP > 4165pg/mL. Moreover, the independent predictive factors of 90-day adverse events included NT-proBNP > 4165pg/mL, age, ACCI score, and CKD. The Kaplan-Meier adverse events curves revealed that the type 2 MI patients with CKD and NT-proBNP > 4165pg/mL had a higher risk than CKD or NT-proBNP > 4165pg/mL alone. Conclusion: Type 2 MI in older pneumonia hospitalization represents a heterogeneous population. Elevated NT-proBNP level and prevalence of CKD are important predictors of type 2 MI and 90-day adverse events in type 2 MI patients.

Cerebrospinal fluid amyloid-ß and cerebral microbleed are associated with distinct neuropsychiatric sub-syndromes in cognitively impaired patients.

BACKGROUND: Neuropsychiatric symptoms (NPS) are prevalent in cognitively impaired individuals including Alzheimer's disease (AD) dementia and mild cognitive impairment (MCI). Whereas several studies have reported the associations between NPS with AD pathologic biomarkers and cerebral small vessel disease (SVD), but it remains unknown whether AD pathology and SVD contribute to different sub-syndromes independently or aggravate same symptoms synergistically. METHOD: We included 445 cognitively impaired individuals (including 316 MCI and 129 AD) with neuropsychiatric, cerebrospinal fluid (CSF) biomarkers (Aß42, p-tau, and t-tau) and multi-model MRI data. Psychiatric symptoms were accessed by using the Neuropsychiatric Inventory (NPI). Visual assessment of SVD (white matter hyperintensity, microbleed, perivascular space, lacune) on MRI images was performed by experienced radiologist. Linear regression analyses were conducted to test the association between neuropsychiatric symptoms with AD pathology and CSVD burden after adjustment for age, sex, education, apolipoprotein E (APOE) ε4 carrier status, and clinical diagnosis. RESULTS: The NPI total scores were related to microbleed (estimate 2.424; 95% CI [0.749, 4.099]; P =0.005). Considering the sub-syndromes, the hyperactivity was associated with microbleed (estimate 0.925; 95% CI [0.115, 1.735]; P =0.025), whereas the affective symptoms were correlated to CSF level of Aß42 (estimate -0.006; 95% CI [-0.011, -0.002]; P =0.005). Furthermore, we found the apathy sub-syndrome was associated with CSF t-tau/Aß42 (estimate 0.636; 95% CI [0.078, 1.194]; P =0.041) and microbleed (estimate 0.693; 95% CI [0.046, 1.340]; P =0.036). In addition, we found a significant interactive effect between CSF t-tau/Aß42 and microbleed (estimate 0.993; 95% CI [0.360, 1.626]; P =0.019) on severity of apathy sub-syndrome. CONCLUSION: Our study showed that CSF Aß42 was associated with affective symptoms, but microbleed was correlated with hyperactivity and apathy, suggesting the effect of AD pathology and SVD on different neuropsychiatric sub-syndromes.

[Age-dependent expression of HSP90 in the hippocampus of APP/PS1 mice].

The present study aims to observe the change in expression of heat shock protein 90 (HSP90) along with amyloid-ß (Aß) and phosphorylated Tau (p-Tau) protein levels in the hippocampus tissue of Alzheimer's disease (AD) transgenic animal model with age. APP/PS1 transgenic mice at age of 6-, 9- and 12-month and C57BL/6J mice of the same age were used. The cognitive abilities of these animals were evaluated using a Morris water maze. Western blot or immunohistochemistry was used to detect the expressions of HSP90 and Aß1-42, as well as the phosphorylation levels of Tau protein in the hippocampus. The hsp90 mRNA levels and the morphology and number of cells in the hippocampus were detected with real-time quantitative polymerase chain reaction (qRT-PCR) and Nissl staining, respectively. The results showed that compared with C57BL/6J mice of the same age, HSP90 and hsp90 mRNA expression were decreased (P < 0.05 or P < 0.01), while Aß1-42 and p-Tau protein levels were increased (P < 0.05 or P < 0.01) in the hippocampal tissue of APP/PS1 transgenic mice. Meanwhile, the decrease in HSP90 and hsp90 mRNA expression (P < 0.05 or P < 0.01), the increase in Aß1-42 and p-Tau levels (P < 0.01 or P < 0.05) in hippocampal tissue and the reduction in behavioral ability showed a progressive development with the advancing of age in the APP/PS1 transgenic mice. In conclusion, in the hippocampal tissue of APP/PS1 mice, the decrease in HSP90 expression and the increase in Aß1-42 and p-Tau levels together with the decline of their cognitive ability are age-dependent.

Novel photocatalytic carbon dots: efficiently inhibiting amyloid aggregation and quickly disaggregating amyloid aggregates.

Amyloid aggregation is implicated in the pathogenesis of various neurodegenerative disorders, such as Alzheimer's disease (AD) and Parkinson's disease (PD). It is critical to develop high-performance drugs to combat amyloid-related diseases. Most identified nanomaterials exhibit limited biocompatibility and therapeutic efficacy. In this work, we used a solvent-free carbonization process to prepare new photo-responsive carbon nanodots (CNDs). The surface of the CNDs is densely packed with chemical groups. CNDs with large, conjugated domains can interact with proteins through π-π stacking and hydrophobic interactions. Furthermore, CNDs possess the ability to generate singlet oxygen species (1O2) and can be used to oxidize amyloid. The hydrophobic interaction and photo-oxidation can both influence amyloid aggregation and disaggregation. Thioflavin T (ThT) fluorescence analysis and circular dichroism (CD) spectroscopy indicate that CNDs can block the transition of amyloid from an α-helix structure to a ß-sheet structure. CNDs demonstrate efficacy in alleviating cytotoxicity induced by Aß42 and exhibit promising blood-brain barrier (BBB) permeability. CNDs have small size, low biotoxicity, good fluorescence and photocatalytic properties, and provide new ideas for the diagnosis and treatment of amyloid-related diseases.

The diagnostic significance of C4d deposits, as an immunohistochemical proof of complement activation, in kidney glomerular pathologies and kidney transplantation.

C4d, a split product of C4 activation in classical and lectin pathways of the complement system activation, has been regarded as a footprint of tissue damage in antibody-mediated rejection in transplantology. The introduction of C4d staining into daily clinical practice aroused an ever-increasing interest in the role of antibody-mediated mechanisms in kidney allograft rejection. However, this marker of complement activation is also important in other various kidney glomerular pathologies such as immunoglobulin A nephropathy, membranoproliferative glomerulonephritis, lupus nephritis, and others. In routine histopathological practice, C4d staining can be done by two histological methods, specifically by immunofluorescence on frozen tissue using monoclonal antibody to C4d (with the downside of unsteady availability of frozen tissue) or by immunohistochemistry using C4d antibodies on formalin-fixed and paraffin-embedded renal tissue. The aim of this narrative review is to summarize recent knowledge about the complement fragment C4d and its significance in different kidney pathologies, focusing on its immunohistochemical detection in renal tissue biopsies. We have supplemented this review with our experience with our proprietary methodology of preparation and practical use of antibodies such as anti-C4d, on a small national level. Immunohistochemical staining for C4d has revolutionized the field of renal histopathology. Despite being a simple diagnostic test, its utility can be of utmost importance, especially in a resource-poor setting where immunofluorescence and frozen tissue may not be available (Fig. 2, Ref. 53). Keywords: C4d deposition, immunohistochemistry, kidney glomerular diseases, kidney transplant, renal tubular damage.

Heparin-induced DRESS syndrome in a paediatric patient and successful anaesthetic management in cardiovascular bypass surgery: case report.

BACKGROUND: Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) Syndrome is a severe adverse drug reaction marked by delayed hypersensitivity reactions causing skin and systemic complications. DRESS diagnosis is challenging due to the variety of clinical presentations and symptom overlap with other conditions. The perioperative period in these patients requires precise pharmacological strategies to prevent complications associated with this syndrome. The treatment of DRESS induced by unfractionated heparin during cardiopulmonary bypass (CPB) surgery presents some challenges that must be considered when selecting an anticoagulant to avoid side effects. In this case, bivalirudin, a direct thrombin inhibitor, is indicated as an alternative to heparin in patients undergoing CPB. However, in contrast to heparin/protamine, there is no direct reversal agent for bivalirudin. CASE PRESENTATION: We report the case of an 11-year-old male diagnosed with native aortic valve endocarditis and thrombosis in his left lower extremity. During valvular replacement surgery, systemic unfractionated heparin was administered. Postoperatively, the patient developed fever, eosinophilia and pruritic rash. Warm shock and elevated alanine transaminase (ALT) and aspartate transaminase (AST) levels followed, leading to the diagnosis of DRESS syndrome. Treatment with methylprednisolone resulted in complete resolution of symptoms. Seven years later, the patient was readmitted due to insufficient anticoagulation and a thrombus in the prosthetic aortic valve, presenting a recurrent DRESS episode due to the administration of unfractionated heparin, which was later replaced with low-molecular-weight heparin during hospitalization. Treatment with corticosteroids and antihistamines was initiated, resulting in the resolution of this episode. Ultimately, the patient required the Ross procedure. During this intervention the anticoagulation strategy was modified, unfractionated heparin was replaced with bivalirudin during the procedure and fondaparinux was administered during the postoperative period. This resulted in stable transaminases levels and no eosinophilia. CONCLUSION: The severity of DRESS Syndrome underscores the importance of early recognition, heightened monitoring, and a comprehensive approach tailored to each patient's needs. This particular case highlights the significance of this approach and may have a substantial clinical impact since it provides alternatives to heparin, such as bivalirudin and fondaparinux, in the anticoagulation strategy of CPB for patients who have a hypersensibility reaction to this medication; thus, enhancing clinical outcomes by minimizing risks linked to adverse drug reactions.

Deciphering S100B Allosteric Signaling: The Role of a Peptide Target, TRTK-12, as an Ensemble Modulator.

Allostery is an essential biological phenomenon in which perturbation at one site in a biomolecule elicits a functional response at a distal location(s). It is integral to biological processes, such as cellular signaling, metabolism, and transcription regulation. Understanding allostery is also crucial for rational drug discovery. In this work, we focus on an allosteric S100B protein that belongs to the S100 class of EF-hand Ca2+-binding proteins. The Ca2+-binding affinity of S100B is modulated allosterically by TRTK-12 peptide binding 25 Å away from the Ca2+-binding site. We investigated S100B allostery by carrying out nuclear magnetic resonance (NMR) measurements along with microsecond-long molecular dynamics (MD) simulations on S100B/Ca2+ with/without TRTK-12 at different NaCl salt concentrations. NMR HSQC results show that TRTK-12 reorganizes how S100B/Ca2+ responds to different salt concentrations at both orthosteric and allosteric sites. The MD data suggest that TRTK-12 breaks the dynamic aromatic and hydrogen-bond interactions (not observed in X-ray crystallographic structures) between the hinge/helix and Ca2+-binding EF-hand loop of the two subunits in the homodimeric protein. This triggers rearrangement in the protein network architectures and leads to allosteric communication. Finally, computational studies of S100B at distinct ionic strengths suggest that ligand-bound species are more robust to the changing environment relative to the S100B/Ca2+ complex.