Discriminating between Homogeneous (AC-1) and Dense Fine Speckled (AC-2) Antinuclear Antibody Patterns: Re-Evaluation of Immunofluorescence Imaging.

Antinuclear antibodies (ANAs) are essential diagnostic markers in systemic autoimmune rheumatic diseases. Among the 30 ANA patterns, homogeneous (AC-1) and dense fine speckled (AC-2) should be focused on owing to their somewhat indistinct presentation in immunofluorescence imaging and distinct correlation with clinical conditions. This study aimed to develop a flowchart to guide discrimination between AC-1 and AC-2 patterns and to re-evaluate ANA samples according to this flowchart to verify its detection ability. We re-evaluated immunofluorescence imaging of 62 ANA blood samples simultaneously subjected to solid-phase assays for autoantibodies against dsDNA, nucleosomes, histones, and DFS70. The results showed statistically significant odd ratios (ORs) of detection of anti-DFS70 using AC-2 after re-evaluation of total samples (OR 101.9, 95% CI 11.7-886.4, p-value < 0.001) and subgroup analysis of patients' samples (OR 53.8, 95% CI 5.9-493.6, p-value < 0.001). The OR of anti-nucleosome/histone/dsDNA detection using AC-1 in re-evaluated data increased to 5.43 (95% CI 1.00-29.61, p-value = 0.05). In the analysis of specific autoantibodies, more than half of the samples with an AC-2 pattern (54.2%) had specific autoantibodies other than anti-DFS70. We conclude that the flowchart for discriminating between AC-1 and AC-2 ANA patterns in this study is a viable practical guide for other laboratories when encountering equivocal ANA results.

Evaluation of Diffusion-Perfusion Mismatch in Acute Ischemic Stroke with a New Automated Perfusion-Weighted Imaging Software: A Retrospective Study.

INTRODUCTION: The aim of this study was to evaluate the accuracy of automated software (iStroke) on magnetic resonance (MR) apparent diffusion coefficient (ADC) and perfusion-weighted imaging (PWI) against ground truth in assessing infarct core, and compare the hypoperfusion volume and mismatch volume on iStroke with those on Food and Drug Administration-approved software (RAPID) in patients with acute ischemic stroke. METHODS: We used the single-volume decomposition method to develop the iStroke (iStroke; Beijing Tiantan Hospital, Beijing, China) software. Patients with ischemic stroke were collected from two educational hospitals in China with MR-PWI performed in the emergency department within 24 h of symptom onset. Infarct core volume was defined as ADC < 620 × 10-6 mm2/s and hypoperfusion volume was defined as Tmax > 6 s. We compared the accuracy of infarct core volume using iStroke and RAPID (iSchema View Inc, Menlo Park, CA) software with ground truth. RESULTS: We included 405 patients with acute ischemic stroke with MR ADC and PWI sequences. The infarct core volume on iStroke (median 2.43 ml, interquartile range [IQR] 0.60-10.32 ml) was not significantly different from the ground truth (median 2.89 ml, IQR 0.77-9.17 ml) (P = 0.07); Bland-Altman curves showed that the core volume of iStroke and RAPID software were comparable with each other on individual agreement with ground truth. The hypoperfusion volume and mismatch volume on iStroke were not statistically different from those on the RAPID software, respectively. In patients with large vessel occlusion (n = 74), the agreement between iStroke and RAPID was substantial (kappa = 0.76) according to DEFUSE 3 criteria (infarct core < 70 ml, mismatch volume ≥ 15 ml, and mismatch ratio ≥ 1.8). CONCLUSIONS: The iStroke automatic processing of ADC and PWI is a reliable software for the identification of diffusion-perfusion mismatch in acute ischemic stroke.

Pregnancy reprograms the epigenome of mammary epithelial cells and blocks the development of premalignant lesions.

Pregnancy causes a series of cellular and molecular changes in mammary epithelial cells (MECs) of female adults. In addition, pregnancy can also modify the predisposition of rodent and human MECs to initiate oncogenesis. Here, we investigate how pregnancy reprograms enhancer chromatin in the mammary epithelium of mice and influences the transcriptional output of the oncogenic transcription factor cMYC. We find that pregnancy induces an expansion of the active cis-regulatory landscape of MECs, which influences the activation of pregnancy-related programs during re-exposure to pregnancy hormones in vivo and in vitro. Using inducible cMYC overexpression, we demonstrate that post-pregnancy MECs are resistant to the downstream molecular programs induced by cMYC, a response that blunts carcinoma initiation, but does not perturb the normal pregnancy-induced epigenomic landscape. cMYC overexpression drives post-pregnancy MECs into a senescence-like state, and perturbations of this state increase malignant phenotypic changes. Taken together, our findings provide further insight into the cell-autonomous signals in post-pregnancy MECs that underpin the regulation of gene expression, cellular activation, and resistance to malignant development.

Total synthesis of tetraacylated phosphatidylinositol hexamannoside and evaluation of its immunomodulatory activity.

Tuberculosis, aggravated by drug-resistant strains and HIV co-infection of the causative agent Mycobacterium tuberculosis, is a global problem that affects millions of people. With essential immunoregulatory roles, phosphatidylinositol mannosides are among the cell-envelope components critical to the pathogenesis and survival of M. tuberculosis inside its host. Here we report the first synthesis of the highly complex tetraacylated phosphatidylinositol hexamannoside (Ac2PIM6), having stearic and tuberculostearic acids as lipid components. Our effort makes use of stereoelectronic and steric effects to control the regioselective and stereoselective outcomes and minimize the synthetic steps, particularly in the key desymmetrization and functionalization of myo-inositol. A short synthesis of tuberculostearic acid in six steps from the Roche ester is also described. Mice exposed to the synthesized Ac2PIM6 exhibit increased production of interleukin-4 and interferon-γ, and the corresponding adjuvant effect is shown by the induction of ovalbumin- and tetanus toxoid-specific antibodies.

Discrimination between Alzheimer's disease and mild cognitive impairment using SOM and PSO-SVM.

In this study, an MRI-based classification framework was proposed to distinguish the patients with AD and MCI from normal participants by using multiple features and different classifiers. First, we extracted features (volume and shape) from MRI data by using a series of image processing steps. Subsequently, we applied principal component analysis (PCA) to convert a set of features of possibly correlated variables into a smaller set of values of linearly uncorrelated variables, decreasing the dimensions of feature space. Finally, we developed a novel data mining framework in combination with support vector machine (SVM) and particle swarm optimization (PSO) for the AD/MCI classification. In order to compare the hybrid method with traditional classifier, two kinds of classifiers, that is, SVM and a self-organizing map (SOM), were trained for patient classification. With the proposed framework, the classification accuracy is improved up to 82.35% and 77.78% in patients with AD and MCI. The result achieved up to 94.12% and 88.89% in AD and MCI by combining the volumetric features and shape features and using PCA. The present results suggest that novel multivariate methods of pattern matching reach a clinically relevant accuracy for the a priori prediction of the progression from MCI to AD.

MRI/SPECT-based diagnosis and CT-guided high-intensity focused-ultrasound treatment system in MPTP mouse model of Parkinson's disease.

Single-photon emission computed tomography (SPECT) of dopamine transporters with (99m)Tc-TRODAT-1 has recently been proposed to offer valuable information for the diagnosis of Parkinson's disease (PD). Furthermore, High-intensity focused ultrasound (HIFU) is a newly developed technique in which the energy of ultrasound wave is directed to a focused spot for the purpose treatment of PD. This study presents a diagnosis and image-guided system using HIFU to treat the mouse with PD under a designed stereotactic frame. The system comprises two key components: an automatic atlas-based SPECT/MRI image registration module for diagnosis and a stereotactic CT-guided module for HIFU treatment. The SPECT/MR image registration here is important in the non-invasive examination of the dopamine concentration in vivo. From the experimental results, the image registration module proves to have comparable performance to that derived from manual drawing by experts. In addition, the stereotactic CT-guided module achieved a positioning accuracy to within 2mm on the average, which is acceptable for the purpose of HIFU treatment.

High-throughput identification of antibacterials against methicillin-resistant Staphylococcus aureus (MRSA) and the transglycosylase.

To identify new transglycosylase inhibitors with potent anti-methicillin-resistant Staphylococcus aureus (MRSA) activities, a high-throughput screening against Staphylococcus aureus was conducted to look for antibacterial cores in our 2M compound library that consists of natural products, proprietary collection, and synthetic molecules. About 3600 hits were identified from the primary screening and the subsequent confirmation resulted in a total of 252 compounds in 84 clusters which showed anti-MRSA activities with MIC values as low as 0.1 µg/ml. Subsequent screening targeting bacterial transglycosylase identified a salicylanilide-based core that inhibited the lipid II polymerization and the moenomycin-binding activities of transglycosylase. Among the collected analogues, potent inhibitors with the IC(50) values below 10 µM against transglycosylase were identified. The non-carbonhydrate scaffold reported in this study suggests a new direction for development of bacterial transglycosylase inhibitors.