Serum Tau Proteins as Potential Biomarkers for the Assessment of Alzheimer's Disease Progression

Total tau (t‐tau) and phosphorylated tau (p‐tau) protein elevations in cerebrospinal fluid (CFS) are well‐established hallmarks of Alzheimer’s disease (AD), while the associations of serum t‐tau and p‐tau levels with AD have been inconsistent across studies. To identify more accessible non‐invasive AD biomarkers, we measured serum tau proteins and associations with cognitive function in age‐matched controls (AMC, n = 26), mild cognitive impairment group (MCI, n = 30), and mild‐AD group (n = 20) according to the Mini‐mental State Examination (MMSE), Clinical Dementia Rating (CDR), and Global Deterioration Scale (GDS) scores. Serum t‐tau, but not p‐tau, was significantly higher in the mild‐AD group than AMC subjects (p < 0.05), and there were significant correlations of serum t‐tau with MMSE and GDS scores. Receiver operating characteristic (ROC) analysis distinguished mild‐AD from AMC subjects with moderate sensitivity and specificity (AUC = 0.675). We speculated that tau proteins in neuronal cell‐derived exosomes (NEX) isolated from serum would be more strongly associated with brain tau levels and disease characteristics, as these exosomes can penetrate the blood‐brain barrier. Indeed, ELISA and Western blotting indicated that both NEX t‐tau and p‐tau (S202) were significantly higher in the mild‐AD group compared to AMC (p < 0.05) and MCI groups (p < 0.01). In contrast, serum amyloid β (Aβ1–42) was lower in the mild‐AD group compared to MCI groups (p < 0.001). During the 4‐year follow‐up, NEX t‐tau and p‐tau (S202) levels were correlated with the changes in GDS and MMSE scores. In JNPL3 transgenic (Tg) mice expressing a human tau mutation, t‐tau and p‐tau expression levels in NEX increased with neuropathological progression, and NEX tau was correlated with tau in brain tissue exosomes (tEX), suggesting that tau proteins reach the circulation via exosomes. Taken together, our data suggest that serum tau proteins, especially NEX tau proteins, are useful biomarkers for monitoring AD progression. © 2020 by the authors. Licensee MDPI, Basel, Switzerland.1

Enhanced expression of microrna-1273g-3p contributes to alzheimer’s disease pathogenesis by regulating the expression of mitochondrial genes

Alzheimer’s disease (AD) is the most common form of dementia in the elderly population, but its underlying cause has not been fully elucidated. Recent studies have shown that microRNAs (miRNAs) play important roles in regulating the expression levels of genes associated with AD development. In this study, we analyzed miRNAs in plasma and cerebrospinal fluid (CSF) from AD patients and cognitively normal (including amyloid positive) individuals. miR-1273g-3p was identified as an AD-associated miRNA and found to be elevated in the CSF of early-stage AD patients. The overexpression of miR-1273g-3p enhanced amyloid beta (Aβ) production by inducing oxidative stress and mitochondrial impairments in AD model cell lines. A biotin-streptavidin pull-down assay demonstrated that miR-1273g-3p primarily interacts with mitochondrial genes, and that their expression is downregulated by miR-1273g-3p. In particular, the miR-1273g-3p-target gene TIMM13 showed reduced expression in brain tissues from human AD patients. These results suggest that miR1273g-3p expression in an early stage of AD notably contributes to Aβ production and mitochondrial impairments. Thus, miR-1273g-3p might be a biomarker for early diagnosis of AD and a potential therapeutic target to prevent AD progression

GJA1 depletion causes ciliary defects by affecting Rab11 trafficking to the ciliary base

The gap junction complex functions as a transport channel across the membrane. Among gap junction subunits, gap junction protein ??1 (GJA1) is the most commonly expressed subunit. A recent study showed that GJA1 is necessary for the maintenance of motile cilia; however, the molecular mechanism and function of GJA1 in ciliogenesis remain unknown. Here, we examined the functions of GJA1 during ciliogenesis in human retinal pigment epithelium-1 and Xenopus laevis embryonic multiciliated-cells. GJA1 localizes to the motile ciliary axonemes or pericentriolar regions beneath the primary cilium. GJA1 depletion caused malformation of both the primary cilium and motile cilia. Further study revealed that GJA1 depletion affected several ciliary proteins such as BBS4, CP110, and Rab11 in the pericentriolar region and basal body. Interestingly, CP110 removal from the mother centriole was significantly reduced by GJA1 depletion. Importantly, Rab11, a key regulator during ciliogenesis, was immunoprecipitated with GJA1 and GJA1 knockdown caused the mislocalization of Rab11. These findings suggest that GJA1 regulates ciliog

Could Fractional Exhaled Nitric Oxide Test be Useful in Predicting Inhaled Corticosteroid Responsiveness in Chronic Cough? A Systematic Review

© 2016 Background Fractional exhaled nitric oxide (FENO) is a safe and convenient test for assessing T H 2 airway inflammation, which is potentially useful in the management of patients with chronic cough. Objective To summarize the current evidence on the diagnostic usefulness of FENO for predicting inhaled corticosteroid (ICS) responsiveness in patients with chronic cough. Methods A systematic literature review was conducted to identify articles published in peer-reviewed journals up to February 2015, without language restriction. We included studies that reported the usefulness of FENO (index test) for predicting ICS responsiveness (reference standard) in patients with chronic cough (target condition). The data were extracted to construct a 2 × 2 accuracy table. Study quality was assessed with Quality Assessment of Diagnostic Accuracy Studies 2. Results We identified 5 original studies (2 prospective and 3 retrospective studies). We identified considerable heterogeneities in study design and outcome definitions, and thus were unable to perform a meta-analysis. The proportion of ICS responders ranged from 44% to 59%. Sensitivity and specificity ranged from 53% to 90%, and from 63% to 97%, respectively. The reported area under the curve ranged from abou t 0.60 to 0.87; however, studies with a prospective design and a lower prevalence of asthma had lower area under the curve values. None measured placebo effects or objective cough frequency. Conclusions We did not find strong evidence to support the use of FENO tests for predicting ICS responsiveness in chronic cough. Further studies need to have a randomized, placebo-controlled design, and should use validated measurement tools for cough. Standardization would facilitate the development of clinical evidence

A Case of Hypersensitivity Syndrome to Both Vancomycin and Teicoplanin

Drug hypersensitivity syndrome to both vancomycin and teicoplanin has not been previously reported. We describe here a 50-yr-old male patient with vertebral osteomyelitis and epidural abscess who developed hypersensitivity syndrome to both vancomycin and teicoplanin. Skin rash, fever, eosinophilia, interstitial pneumonitis, and interstitial nephritis developed following the administration of each drug, and resolved after withdrawing the drugs and treating with high dose corticosteroids. The vertebral osteomyelitis was successfully treated with 6-week course of linezolid without further complications. Skin patch tests for vancomycin and teicoplanin was done 2 months after the recovery; a weak positive result for vancomycin (10% aq.,+at D2 and +at D4 with erythema and vesicles; ICDRG scale), and a doubtful result for teicoplanin (4% aq.-at D2 and±at D4 with macular erythema; ICDRG scale). We present this case to alert clinicians to the hypersensitivity syndrome that can result from vancomycin and teicoplanin, with possible cross-reactivity, which could potentially be life-threatening

Cerebrospinal Fluid Biomarkers for the Diagnosis of Prodromal Alzheimer’s Disease in Amnestic Mild Cognitive Impairment

Background/Aims: Disease-modifying therapy for Alzheimer’s disease (AD) has led to a need for biomarkers to identify prodromal AD and very early stage of AD dementia. We aimed to identify the cutoff values of cerebrospinal fluid (CSF) biomarkers for detecting prodromal AD. Methods: We assessed 56 patients with amnestic mild cognitive impairment (aMCI) who underwent lumbar puncture. Additionally, 87 healthy elderly individuals and 34 patients with AD dementia served as controls. Positron emission tomography was performed using florbetaben as a probe. We analyzed the concentration of Aβ1–42, total tau protein (t-Tau), and tau protein phosphorylated at threonine 181 (p-Tau181) in CSF with INNOTEST enzyme-linked immunosorbent assay. Results: For the detection of prodromal AD in patients with aMCI, the cutoff values of CSF Aβ1–42, t-Tau, and p-Tau181 were 749.5 pg/mL, 225.6 pg/mL, and 43.5 pg/mL, respectively. To discriminate prodromal AD in patients with aMCI, the t-Tau/Aβ1–42 and ­p-Tau181/Aβ1–42 ratios defined cutoff values at 0.298 and 0.059, respectively. Conclusions: CSF biomarkers are very useful tools for the differential diagnosis of prodromal AD in aMCI patients. The concentration of CSF biomarkers is well correlated with the stages of the AD spectrum

Hypereosinophilia Presenting as Eosinophilic Vasculitis and Multiple Peripheral Artery Occlusions without Organ Involvement

We report here a case with hypereosinophilia and peripheral artery occlusion. A 32-yr-old Korean woman presented to us with lower extremity swelling and pain. Angiography revealed that multiple lower extremity arteries were occlusive. The biopsy specimen showed perivascular and periadnexal dense eosinophilic infiltration in dermis and subcutaneous adipose tissue. Laboratory investigations revealed a persistent hypereosinophilia. She was prescribed prednisolone 60 mg daily. Her skin lesion and pain were improved and the eosinophil count was dramatically decreased. After discharge, eosinophil count gradually increased again. Cyanosis and pain of her fingers recurred. She had been treated with cyclophosphamide pulse therapy. Her eosinophilia was decreased, but the cyanosis and tingling sense were progressive. The extremity arterial stenoses were slightly progressed. Skin biopsy showed perivascular eosinophilic infiltration in the dermis and CD40 ligand (CD40L) positive eosinophilic infiltration. The serum TNF-α was markedly increased. These results suggest that CD40L (a member of TNF-α superfamily) could play a role in the inflammatory processes when eosinophil infiltration and activation are observed. We prescribed prednisolone, cyclophosphamide, clopidogrel, cilostazol, beraprost and nifedipine, and she was discharged

Corporatism as a process of working class containment and roll-back: The recent experiences of South Africa and South Korea

In this article we argue that recent debates in the corporatist literature about whether corporatism is best understood as a process of structured interest representation or political dialogue miss the point as to corporatism's central task - the shift of material resources and power away from the working class to the capitalist class, in which two processes are evident - containment and roll-back. We discuss these processes in the context of successive waves of corporatism in Western Europe from the 1940s to the 1990s before moving on to an analysis of the contrasting fortunes of corporatism in South Africa and South Korea during democratic transition. We conclude that the ability of corporatism to carry out the processes of containment and roll back in these two cases have been dependent on the existence (or absence) of supportive prior political relationships between organised labour and the state

The Relation of Menarcheal Age to Anthropometric Profiles in Korean Girls

The aim of this study was to represent the trend of early menarche and to assess the association of age at menarche with anthropometric profiles of Korean children and adolescents. A cross sectional survey was conducted with 13,371 girls aged 10 to 18 yr, recruited nationwide from April, 2005 to March, 2006. Height, weight and waist circumference of the subjects were measured; and the subjects self-reported their ages at menarche. We found that the menarcheal girls were taller (P<0.05 for the girls between 10 and 14 yr) and heavier (P<0.05 for the girls between 10 and 18 yr) than non-menarcheal ones. Menarcheal girls also showed higher body mass index (BMI), and greater waist circumference than non-menarcheal ones. Significant differences were represented according to the age at menarche in terms of BMI, waist circumference, % body fat mass, waist hip ratio and neck circumference as well as height and weight (P<0.05). In conclusion, girls who matured early were taller and heavier in early adolescence than those who matured later