Antiphospholipid antibodies in autoimmune thyroid diseases

BackgroundAntiphospholipid (aPL) antibodies have been reported in several autoimmune diseases. The aim of this study was to evaluate the frequency of aPL (anti‐cardiolipin antibodies (aCL) and anti‐β2 glycoprotein I antibodies (aβ2GPI)) in patients with autoimmune thyroid diseases (AITD).MethodsOne hundred and ninety‐five patients with AITD (139 Hashimoto''s thyroiditis (HT) patients and 56 Graves'' disease (GD) patients) and 90 healthy blood donors (HBD) were studied. IgG, IgA and IgM aCL and aβ2GPI were determined by ELISA.ResultsOne hundred fifty‐four AITD patients were women and 41 were men. Fifty‐six healthy subjects were women and 34 were men. The median age of patients and the control group was 45 and 38.5 years, respectively. The frequency of aPL was significantly higher in patients with AITD and in patients with HT than in HBD (33.3% vs 11.1%, p < 10⁻³ and 38.1% vs 11.1%, p < 10⁻³). The frequency of aPL in GD was significantly lower than in HT (21.4% vs 38.1%, p = 0.025). In patients with HT, aβ2GPI (34.5%) was significantly more frequent than aCL (13.6%) (p < 10⁻³). The frequency of aβ2GPI was significantly higher in patients with HT than in healthy population (34.5% vs 11.1%, p < 10⁻³). In HT patients, IgA isotype of aβ2GPI was significantly more common than in HBD and in GD patients (27.3% vs 7.8%, p < 10⁻³ and 27.3% vs 12.5%, p = 0.02, respectively).Conclusionaβ2GPI and not aCL were frequent in AITD. IgA was the predominant isotype of aβ2GPI. aβ2GPI‐IgA was more frequent in HT than in GD.     

Blood Th17 cells and IL‐17A as candidate biomarkers estimating the progression of cognitive impairment in stroke patients

BackgroundT helper (Th) cells regulate immunity and inflammation to engage in cognitive impairment in several neurological diseases, while their clinical relevance in stroke patients is not clear. The current study intended to assess the relationship of Th1 cells, Th17 cells, interferon‐gamma (IFN‐γ), and interleukin (IL)‐17A with cognitive function in stroke patients.MethodsOne hundred twenty stroke patients and 40 controls were enrolled in this muticenter study. Th1 and Th17 cells in peripheral blood were assessed by flow cytometry; meanwhile, IFN‐γ and IL‐17A in serum were detected by enzyme‐linked immunosorbent assay. Cognitive function of stroke patients was evaluated by Mini‐Mental State Examination (MMSE) score at enrollment (baseline), year 1, year 2, and year 3.ResultsTh1 cells (p = 0.037) and IFN‐γ (p = 0.048) were slightly increased, while Th17 cells (p < 0.001) and IL‐17A (p < 0.001) were greatly elevated in stroke patients compared with controls. Th17 cells (r _s = −0.374, p < 0.001) and IL‐17A (r _s = −0.267, p = 0.003) were negatively correlated with MMSE score at baseline, but Th1 cells and IFN‐γ were not. Meanwhile, Th17 cells (p = 0.001) and IL‐17A (p = 0.024) were increased in patients with cognitive impairment compared to those without cognitive impairment. Notably, Th17 cells were positively associated with 1‐year (r _s = 0.331, p < 0.001), 2‐year (r _s = 0.261, p = 0.006), and 3‐year (r _s = 0.256, p = 0.011) MMSE decline; IL‐17A was positively correlated with 1‐year (r _s = 0.262, p = 0.005), 2‐year (r _s = 0.193, p = 0.045), but not 3‐year MMSE decline. However, both Th1 cells and IFN‐γ were not linked with MMSE decline.ConclusionTh17 cells and IL‐17A estimate the progression of cognitive impairment in stroke patients.     

中药治疗与传统认知训练联合虚拟技术对阿尔兹海默病患者的疗效评价

目的:运用中药辨证治疗与传统认知训练,联合虚拟现实情景互动技术,对轻度阿尔兹海默病患者进行早期认知干预,观察其疗效。方法:将符合纳入条件的68例患者,随机分为对照组(n=34例)和治疗组(n=34例),均予每周6天、连续6个月的治疗,对照组给予中药辨证论治结合传统认知训练,治疗组在对照组的基础上联合虚拟现实情景互动(Anokan-VR)技术治疗。采用简易智能精神状态检查量表(MMSE),功能独立性评定(FIM)量表、韦氏记忆测验修订版(WMS,1999)对两组患者治疗前及治疗后的疗效进行评价比较。结果:治疗前后两组的MMSE评分、FIM评分、WMS评分,均有显著性变化(P0.05);且治疗后治疗组的效果明显优于对照组(P0.05或P0.01)。结论:传统认知训练结合中药辨证论治,可改善轻度阿尔兹海默病患者的认知功能,在此基础上联合虚拟现实情景互动技术,疗效更佳。     

Lung carcinoma–associated cognitive impairment in a patient with Alzheimer’s disease pathology: A case report

A patient with Alzheimer''s disease (AD) pathology when cognitive impairment is detected tends to be diagnosed with AD. However, before diagnosing, we make an effort to exclude other diseases, for example, carcinoma.     

Exploring potential serum levels of Homocysteine,interleukin‐1 beta,and apolipoprotein B 48 as new biomarkers for patients with ischemic stroke

BackgroundStroke is the second leading cause of death worldwide with heterogeneous characteristics. The subtypes of stroke are due to different pathophysiological regulations and causes. This study aimed to investigate the correlation of serum levels of apolipoprotein B 48, interleukin‐1β and Homocysteine with BMI in patients with ischemic stroke (IS).MethodsOver one hundred controls (120) and an equal number of IS patients, including 31 women and 89 men, were recruited to participate in the case‐control study conducted at Imam Reza Hospital (Tabriz, Iran) from February 2019 to March 2020. We measured serum levels of apolipoprotein B 48, interleukin‐1β, and Homocysteine. Receiver operating characteristic analysis (ROC) was performed to evaluate the diagnostic value of these indices in patients and control groups.ResultsThe mean serum levels of apolipoprotein B 48, interleukin‐1β, and Homocysteine, were significantly increased in the experimental group compared to the control group with a p‐value of 0.001. The ROC curve analysis showed that the area under the curve for apo B48, IL −1β, hs‐CRP, and Homocysteine serum levels were 0.94, 0.98, 0.99, and 1, respectively.ConclusionsThe results of our current study show that the determination of serum levels of apolipoprotein B 48, interleukin‐1β, and Homocysteine can potentially be used to monitor and diagnose IS patients. However, there was no statistically significant correlation between serum levels of apolipoprotein B 48, interleukin 1β and Homocysteine and BMI in the patient group. However, there was a statistically significant inverse correlation between serum levels of high‐sensitivity C‐reactive protein (hs‐CRP) and BMI in the patient group.     

Altered retinol status and expression of retinol-related proteins in streptozotocin-induced type 1 diabetic model rats

Diabetes is a metabolic disorder characterized by chronic hyperglycemia. Advanced diabetes is associated with severe complications and impaired nutritional status. Here, we assessed the expression of retinol-associated proteins, including β-carotene 15,15''-monooxygenase (BCMO), lecithin:retinol acyltransferase (LRAT), aldehyde dehydrogenase (ALDH), and cytochrome P450 26A1 (CYP26A1), and measured retinol levels in the plasma and liver of streptozotocin (STZ)-induced type 1 diabetic model rats. Compared to the levels in the control rats, retinol levels in the plasma and liver of STZ rats were decreased and increased, respectively. Hepatic expression of the LRAT gene in STZ rats was lower than that in the controls. In the liver of STZ rats, the expression of ALDH1A1, a retinal metabolizing enzyme was higher, whereas ALDH1A2 expression was lower than in the controls. Hepatic CYP26A1 expression in STZ rats was significantly higher than in the control rats. BCMO expression levels in the liver and intestine of STZ rats were much lower than those of the controls. Altered BCMO expression might affect retinol status. It is considered that the metabolic availability of retinol was lessened despite the accelerated catabolism of retinol; therefore, retinol mobilization may be unbalanced in the liver of rats in the type 1 diabetic state.     

Genetic research and clinical analysis of β‐globin gene cluster deletions in the Chinese population of Fujian province: A 14‐year single‐center experience

BackgroundHeterozygotes of HPFH and δβ thalassemia are clinically asymptomatic or have mild hemoglobin (Hb) values. However, when both HPFH and δβ‐thalassemia are coinherited with heterozygous β‐thalassemia, patients may progress to a clinical phenotype of thalassemia intermedia or thalassemia major. The purpose of this study was to characterize the genotypes and analyze the phenotypes of these disorders in Fujian Province, to offer advice for genetic counseling and accurate prenatal diagnosis in this region. A total of 55 001 subjects were participated in thalassemia screening. 142 subjects with HbF levels ≥10%, before the blood transfusion, were selected for further investigation.MethodsMultiplex ligation‐dependent probe amplification (MLPA) and Gap‐PCR were used to screen for three β‐globin gene cluster deletions: Chinese ^Gγ(^Aγδβ)⁰ thalassemia and Southeast Asia HPFH (SEA‐HPFH) deletion and 1357 bp deletion (NG‐000007.3:g.69997‐71353 del 1357).ResultsA total of 142 patients with HbF (≥10%) were enrolled to characterize the molecular basis of β‐globin gene cluster deletions in our study; 22 cases 0.04% (22/55 001) were definitively diagnosed with β‐globin gene cluster deletions. Ten cases were heterozygous for the Chinese ^Gγ(^Aγδβ)⁰‐thal mutations, 10 cases were heterozygous for SEA‐HPFH, and one case was compound heterozygous for SEA‐HPFH and the α‐thal mutation. The 1357 bp deletion (NG‐000007.3:g.69997‐71353 del 1357) was detected in one case. Moreover, the hemoglobin A₂ levels in patients who were heterozygous for Chinese ^Gγ(^Aγδβ)⁰‐thal were statistically lower than in cases with SEA‐HPFH deletion(p < 0.05).ConclusionIn Fujian Province, the prevalence of common β‐globin gene cluster deletions was 0.04%. What''s more, the most common β‐globin cluster deletions are the Chinese ^Gγ(^Aγδβ)⁰ and SEA‐HPFH.     

Determination of diagnostic threshold in harmonization and comparison of clinical utility for five major antiphospholipid antibody assays used in Japan

BackgroundAnticardiolipin antibodies (aCL) and anti‐β₂‐glycoprotein I antibodies (aβ₂GPI) are essential in diagnosing antiphospholipid syndrome (APS) according to the international APS guideline. Five commercial assays for aCL and aβ₂GPI are available in Japan, but their test results are quite discordant. For harmonization of diagnosing APS, upper reference limit (URL) and diagnostic accuracy of each assay were evaluated and compared by testing common sets of specimens across all assays.MethodsWe evaluated two manual and three automated assays for aCL and aβ₂GPI of IgG‐ and IgM classes. 99%URL (the upper limit of reference interval: as per guideline) together with 97.5%URL were determined by testing sera from 198 to 400 well‐defined healthy subjects. Both URLs were compared with the cutoff values, which were determined based on ROC analysis by testing 50 each of plasma specimens from patients with/without APS. Diagnostic accuracy was evaluated as area under curve (AUC) of the ROC curve.ResultsA variable degree of discrepancy between URLs and the cutoff values was observed, which was partly attributable to between‐year assay variability. 97.5%URLs were set lower and closer to the cutoff values than 99%URLs. For all assays, diagnostic accuracies of both aβ₂GPI‐IgG and aCL‐IgG were generally high (AUC: 0.84−0.93); whereas those for IgM‐class assays were low (AUC: 0.57−0.67), implicating its utility is limited to rare IgG negative APS cases.ConclusionTo ensure harmonized APS diagnosis, the diagnostic thresholds of the five assays were evaluated by common procedures. Contrary to the guideline, 97.5%URL is rather recommended for diagnosing APS, which showed a closer match to the cutoff value.     

Immune‐mediated thrombotic thrombocytopenic purpura in a Jehovah’s Witness – Effectiveness of incorporating extracorporeal immunoadsorption to caplacizumab,steroids and rituximab

We report the case of a Jehovah''s Witness adolescent patient with immune‐mediated thrombotic thrombocytopenic purpura after SARS‐Cov2 infection successfully treated without therapeutic plasma exchange (TPE) using caplacizumab, corticosteroids, rituximab, and extracorporeal immunoadsorption (EIA). Further patients for whom TPE is not an option might benefit from this approach.     

Current state of technologies and recognition of anti‐SSA/Ro antibodies in China: A multi‐center study

BackgroundPrevious studies have demonstrated that Ro60 and Ro52 have different clinical implications, and anti‐Ro52 antibodies are an independent serum marker of systemic autoimmune diseases, including Sjögren''s syndrome. Many different assays have been adopted to detect anti‐Sjögren''s syndrome antigen A (SSA)/Ro antibodies, while to date no specific approach has been recommended as optimal for anti‐SSA/Ro antibody testing. Herein, we performed a multi‐center study to explore the current clinical utility of different strategies for anti‐SSA/Ro antibody testing in China.MethodsTwenty‐one tertiary care centers were included in this questionnaire‐based study. The self‐administered questionnaire mainly includes testing methods for anti‐SSA/Ro antibodies, reporting system of results, and interpretation of results by clinicians.ResultsSix different methods were applied to detect anti‐SSA/Ro antibodies in the 21 centers. Line immunoassay (eight different commercial kits) was the most frequently adopted method (21/21, 100%), with different cutoff values and strategies for intensity stratification. There were two reporting systems: One was reported as “anti‐SSA antibodies” and “anti‐Ro52 antibodies” (12/21, 57%), while the other was “anti‐SSA/Ro60 antibodies” and “anti‐SSA/Ro52 antibodies” (9/21, 43%). Notably, six centers (29%) considered either positive anti‐Ro60 or anti‐Ro52 antibodies as positive anti‐SSA antibodies, all of which adopted the latter reporting system.ConclusionSignificant variabilities existed among anti‐SSA/Ro assays. Nearly 30% of centers misinterpreted the definition of positive anti‐SSA antibodies, which may be attributed to the confusing reporting systems of line immunoassay. Therefore, we advocate standardization of the nomenclature of anti‐SSA/Ro antibodies, changing the “anti‐SSA/Ro52” label in favor of the “anti‐Ro52” antibodies for a clear designation.     

In vitro and in vivo characterization of several functionalized ultrasmall particles of iron oxide,vectorized against amyloid plaques and potentially able to cross the blood–brain barrier: toward earlier diagnosis of Alzheimer's disease by molecular imaging

Alzheimer's disease (AD) is a neurodegenerative disorder most often diagnosed 10 years after its onset and development. It is characterized by the accumulation of amyloid‐β peptide (ABP) into amyloid plaques between nerve cells, which produces a massive local neurodegeneration. Molecular magnetic resonance imaging allows diagnosis of AD by showing ABP accumulation in the brain. The ultrasmall particles of iron oxide (USPIO) derivatives proposed in the present work were functionalized with peptides that present an affinity for ABP, independently of its state of aggregation. Their nanomolar K_d* confirms the high affinity of our vectorized contrast agents (VCA) for ABP and therefore their high labeling potential, specificity and sensitivity. Their lack of toxicity has been demonstrated, both by in vitro studies using the MTT method on several cell types, and by in vivo investigations with assessment of renal and hepatic biomarkers and by histopathology evaluation. The results of biodistribution studies corroborated by MRI demonstrate that USPIO‐PHO (USPIO coupled to peptide C‐IPLPFYN‐C) are able to cross the blood–brain barrier without any facilitating strategy, and accumulates in the brain 90 min after its injection in NMRI mice. None of the USPIO derivatives were found in any organs one week after administration. To conclude, USPIO‐PHO seems to have a genuine potential for labeling amyloid plaques in the brain; it has a nanomolar binding affinity, no toxic effects, and its elimination half‐life is about 3 h. Further tests will be made on transgenic mice, aimed at confirming the potential of early AD diagnosis using our VCA. Copyright © 2014 John Wiley & Sons, Ltd.     

A New Monoclonal Antibody,mAb 4A12, Identifies a Role for the Glycosaminoglycan (GAG) Binding Domain of RANTES in the Antiviral Effect against HIV-1 and Intracellular Ca2+ Signaling

The β-chemokine RANTES (regulated on activation, normal T cell expressed and secreted) suppresses the infection of susceptible host cells by macrophage tropic strains of HIV-1. This effect is attributed to interactions of this chemokine with a 7-transmembrane domain receptor, CCR5, that is required for virus–cell fusion and entry. Here we identify domains of RANTES that contribute to its biological activities through structure–function studies using a new monoclonal antibody, mAb 4A12, isolated from mice immunized with recombinant human RANTES. This monoclonal antibody (mAb) blocked the antiviral activity of RANTES in infectivity assays with HIV-1_Bal, and inhibited the mobilization of intracellular Ca²⁺ elicited by RANTES, yet recognized this chemokine bound to cell surfaces. Epitope mapping using limited proteolysis, reversed phase high-performance liquid chromatography, and mass spectrometry suggest that residues 55–66 of RANTES, which include the COOH-terminal α-helical region implicated as the glycosaminoglycan (GAG) binding domain, overlap the determinant recognized by mAb 4A12. This is supported by affinity chromatography studies, which showed that RANTES could be eluted specifically by heparin from a mAb 4A12 immunoaffinity matrix. Removal of cell surface GAGs by enzymatic digestion greatly reduced the ability of mAb 4A12 to detect RANTES passively bound on cell surfaces and abrogated the ability of RANTES to elicit an intracellular Ca²⁺ signal. Taken together, these studies demonstrate that the COOH-terminal α-helical region of RANTES plays a key role in GAG-binding, antiviral activity, and intracellular Ca²⁺ signaling and support a model in which GAGs play a key role in the biological activities of this chemokine.     

Recent advances in the multitarget‐directed ligands approach for the treatment of Alzheimer's disease

With 27 million cases worldwide documented in 2006, Alzheimer's disease (AD) constitutes an overwhelming health, social, economic, and political problem to nations. Unless a new medicine capable to delay disease progression is found, the number of cases will reach 107 million in 2050. So far, the therapeutic paradigm one‐compound‐one‐target has failed. This could be due to the multiple pathogenic mechanisms involved in AD including amyloid β (Aβ) aggregation to form plaques, τ hyperphosphorylation to disrupt microtubule to form neurofibrillary tangles, calcium imbalance, enhanced oxidative stress, impaired mitochondrial function, apoptotic neuronal death, and deterioration of synaptic transmission, particularly at cholinergic neurons. Approximately 100 compounds are presently been investigated directed to single targets, namely inhibitors of β and γ secretase, vaccines or antibodies that clear Aβ, metal chelators to inhibit Aβ aggregation, blockers of glycogen synthase kinase 3β, enhancers of mitochondrial function, antioxidants, modulators of calcium‐permeable channels such as voltage‐dependent calcium channels, N‐methyl‐D ‐aspartate receptors for glutamate, or enhancers of cholinergic neurotransmission such as inhibitors of acetylcholinesterase or butyrylcholinesterase. In view of this complex pathogenic mechanisms, and the successful treatment of chronic diseases such as HIV or cancer, with multiple drugs having complementary mechanisms of action, the concern is growing that AD could better be treated with a single compound targeting two or more of the pathogenic mechanisms leading to neuronal death. This review summarizes the current therapeutic strategies based on the paradigm one‐compound‐various targets to treat AD. A treatment that delays disease onset and/or progression by 5 years could halve the number of people requiring institutionalization and/or dying from AD. © 2011 Wiley Periodicals, Inc. Med Res Rev