Eriocitrin Alleviates Inflammation and Oxidative Stress in Subarachnoid Hemorrhage by Regulating DUSP14.

BACKGROUND: Inflammation and oxidative stress (OS) are major causes of aneurysmal subarachnoid hemorrhage (aSAH)-induced early brain injury (EBI). Eriocitrin (EC), a flavonoid compound, has anti-inflammatory and antioxidant actions. However, there is still no relevant studies on the role of EC in SAH. Accordingly, this research aims to clarify the anti-OS and anti-inflammatory efficacy of EC in SAH. METHOD: Rat SAH model was established in vivo and administered with Eriocitrin (25 mg/kg). In vitro, BV2 cells were exposed to oxyhemoglobin (OxyHb) for 24 hours and pretreated with Eriocitrin (1 uM/mL, 2 uM/mL, 4 uM/mL) for 30 minutes. Water maze experiments and neurological function scores were conducted to assess cognitive and motor function. TdT-mediated dUTP Nick-End Labeling (TUNEL) staining was used to detect cortical cell apoptosis. Enzyme-linked immunosorbent assay (ELISA) and polymerase chain reaction (PCR) were used to detect the inflammatory factors and malondialdehyde (MDA), as well as the expression of superoxide dismutase (SOD) and glutathione peroxidase (GSH-px). Western blots were used to semi quantify nuclear factor erythroid-2-related factor 2 (Nrf2), nuclear factor-κB (NF-κB), dual specificity phosphatase 14 (DUSP14) expression. RESULTS: The findings suggest that EC (25 mg/kg) reduced SAH-induced central nervous system (CNS) damage, neuronal apoptosis, inflammatory reactions and OS. Regarding a mechanistic study, EC enhanced Nrf2 and NF-κB by increasing DUSP14 activation, thereby reducing the inflammatory cytokines interleukin (IL)-1ß, tumor necrosis factor (TNF)-α, and IL-6. In addition, EC decreased MDA while markedly elevating SOD and enhancing GSH-px. Furthermore, specifically inhibiting DUSP14 expression via using protein-tyrosine-phosphatase (PTP) inhibitor IV, neutralized the protective action of EC and aggravated inflammation and OS. In vitro experiments of OxyHb-induced BV2 cells revealed that EC promoted Nrf2 while markedly suppressing NF-κB by increasing DUSP14 activation, thereby reducing the concentrations of the above inflammatory cytokines. Moreover, EC decreased MDA while evidently increasing SOD and GSH-px. CONCLUSION: In summary, this paper lays a theoretical grounding for EC treatment of SAH-induced inflammatory reactions and OS by regulating DUSP14.

High-dimensional immune profiling using mass cytometry reveals IL-17A-producing γδ T cells as biomarkers in patients with T-cell-activated idiopathic severe aplastic anemia.

Severe aplastic anemia (SAA) is a bone marrow failure syndrome characterized by activated T cells. Features of T-cell activation in the pathophysiology of SAA remain unknown. To understand T cell activation states, we investigated the atlas of peripheral immune cells and the secreted cytokine network with single cell mass cytometry analysis. We found decreased γδ T-cell frequencies in all patients with SAA, together with a significantly increased proportion of interleukin (IL)-17A-producing cell subsets. Cytokine network analysis of immune cells showed significant positive relationship between IL and 17A production from immune cells and disease severity of severe aplastic anemia. On separating SAA into two distinct subgroups based on T-cell activation stage, the proportion of γδ T cells tended to decrease in the T-cell-activated SAA group compared with non-T-cell-activated group. And the proportion of IL-17A-producing γδ T cells (γδT17) within γδ T cells was newly found to be significantly higher in the T-cell-activated SAA group, implying that IL-17A production by γδ T cells was associated with T-cell activation. Overall, our study revealed a role of γδT17 cells in mediating autoreactive T-cell activation in SAA and provided a novel diagnostic indicator for monitoring autoreactive T-cell activation status during the progression of aplastic anemia in the clinic.

A validated liquid chromatography-tandem mass spectrometry method for the determination of l-hyoscyamine in human plasma: Application in a clinical study.

Atropine is a racemic mixture of d- and l-hyoscyamine, but only l-hyoscyamine is the effective ingredient. In this study, a new, sensitive, stable, and selective LC/MS assay was developed for the determination of l-hyoscyamine and applied to a clinical study. The parent-product (m/z) transition pair of l-hyoscyamine was 290.1 → 124.1. Chromatographic separations were performed using a chiral MZ column (250 mm × 4.6 mm, 5.0 µm) by a stepwise gradient elution mode with n-hexane, isopropanol, and diethylamine as mobile phases. l-Hyoscyamine in human plasma was extracted by liquid-liquid extraction. This assay displayed a good linearity over a concentration range of 20.0-400 pg/mL for l-hyoscyamine. The accuracy of the validation assay for l-hyoscyamine ranged from -2.7% to 4.5%, and the precision was within 6.3% coefficient of variation. l-Hyoscyamine in human plasma remained stable at different storage conditions. The method has been successfully applied to plasma samples obtained from a safety study in humans.

Favorable effect after single treatment session of 755-nm-picosecond laser with a diffractive optic lens on facial wrinkles and pore size in Asians.

OBJECTIVES: Laser therapy has become one of the mainstay treatments for improving signs of aging including wrinkles, large pores, and skin pigmentation. However, in patients with pigmented skin, an increase in complications including post-inflammatory hyperpigmentation (PIH) has been noted. The purpose of this study is to investigate not only the safety profile of 755-nm picosecond laser with diffractive lens array (DLA) at approximately 2250 pulses on the face in people with darker skin, but also to evaluate its efficacy in treating wrinkles and pore sizes after one treatment session among different age groups. METHODS: This single-center, retrospective study enrolled patients between age 22 and 65 with both facial wrinkles and enlarged pore sizes. A total of 46 patients (7 male, 39 female, mean age 43) with Fitzpatrick skin types III and IV were enrolled. Two independent data-blinded dermatologists assessed and scored the improvements of patients' wrinkles and pore sizes using photographs. RESULTS: After one treatment session, statistically significant improvements were observed in lateral canthal wrinkles (p < 0.001) and facial wrinkles (p = 0.014). In addition, greater percentage of the patients from the aged group (50-65 years) showed clinically significant improvement as compared with the younger group. CONCLUSIONS: For patients with type III and IV skin, one session of DLA picosecond laser treatment at around 2250 pulses to the face is safe and effective for clinically meaningful improvement of the wrinkles and pore sizes, especially for the patients from 50- to 65-years of age.

Simple procedure to evaluate mid-face sagging: A pilot study from Taiwan.

An easy and objective way to evaluate mid-face sagging is marking straight lines between the nasal alar and the mandibular angle, one in the supine and the other in an upright position. The maximal distance between the two lines drawn is measured. Statistic analyses shows that this maximum distance demonstrates positive correlation with age and body mass index that reflects the level of mid-face sagging. This simple method may be utilised to evaluate the effect of anti-ageing treatment on the face in the context of mid-face sagging.

Novel multi-drugs incorporating hybrid-structured nanofibers enhance alkylating agent activity in malignant gliomas.

BACKGROUND: Malignant gliomas (MGs) are highly chemotherapy-resistant. Temozolomide (TMZ) and carmustine (BiCNU) are alkylating agents clinically used for treating MGs. However, their effectiveness is restrained by overexpression of the DNA repair protein O6-methylguanine-DNA methyltransferase (MGMT) in tumors. O6-benzylguanine (O6-BG) is a nonreversible inhibitor of MGMT, it promotes the cytotoxicity of alkylating chemotherapy. The authors have developed a hybrid-structured nanofibrous membrane (HSNM) that sequentially delivers high concentrations of O6-BG, BiCNU, and TMZ in an attempt to provide an alternative to the current therapeutic options for MGs. METHODS: The HSNMs were implanted onto the cerebral surface of pathogen-free rats following surgical craniectomy, while the in vivo release behaviors of O6-BG, TMZ, and BiCNU from the HSNMs were explored. Subsequently, the HSNMs were surgically implanted onto the brain surface of two types of tumor-bearing rats. The survival rate, tumor volume, malignancy of tumor, and apoptotic cell death were evaluated and compared with other treatment regimens. RESULTS: The biodegradable HSNMs sequentially and sustainably delivered high concentrations of O6-BG, BiCNU, and TMZ for more than 14 weeks. The tumor-bearing rats treated with HSNMs demonstrated therapeutic advantages in terms of retarded and restricted tumor growth, prolonged survival time, and attenuated malignancy. CONCLUSION: The results demonstrated that O6-BG potentiates the effects of interstitially transported BiCNU and TMZ. Therefore, O6-BG may be required for alkylating agents to offer maximum therapeutic benefits for the treatment of MGMT-expressing tumors. In addition, the HSNM-supported chemoprotective gene therapy enhanced chemotherapy tolerance and efficacy. It can, therefore, potentially provide an improved therapeutic alternative for MGs.

Acute parkinsonism as an unexpected consequence of pituitary adenoma resection: A case report.

INTRODUCTION: Transsphenoidal resection of pituitary tumors is a surgery performed through the nose and sphenoid sinus to remove pituitary tumors. Disorders of sodium balance are common after transsphenoidal surgery involving the pituitary gland. Here, we report the clinical features of an original case of acute onset parkinsonism later confirmed to be secondary to transsphenoidal resection of pituitary adenoma. PATIENT CONCERNS: A 36-year-old female had received transsphenoidal pituitary resection for pituitary adenoma. Eight days after the surgery, she suffered from acute onset general weakness and nausea/vomiting. She was diagnosed with hyponatremia for which she was treated. Acute onset ataxia, bilateral hand tremor, and dysarthria were then noted on the 4th day of hyponatremia treatment. DIAGNOSIS: Based on history, clinical manifestation, and MRI brain images, a diagnosis of acute parkinsonism caused by isolated extrapontine myelinolysis (EPM) was made. INTERVENTIONS: Patient was treated with levodopa/carbidopa. OUTCOMES: Patient's symptoms and signs improved gradually and 2 month follow-up MRI brain showed significant resolution of the bilateral lentiform nuclei hyperintensities on the T2-weighted images. Her neurological deficits had subsided completely. LESSONS: This case highlights an unexpected association between transsphenoidal resection of pituitary tumors and acute parkinsonism which is a treatable manifestation of EPM. Correction of hyponatremia following transsphenoidal pituitary resections should be preceded cautiously because even gradual correction of hyponatremia can produce myelinolysis.

Multi-factors including Inflammatory/Immune, Hormones, Tumor-related Proteins and Nutrition associated with Chronic Prostatitis NIH IIIa+b and IV based on FAMHES project.

Chronic prostatitis (CP) is a complex disease. Fragmentary evidence suggests that factors such as infection and autoimmunity might be associated with CP. To further elucidate potential risk factors, the current study utilized the Fangchenggang Area Male Health and Examination Survey (FAMHES) project; where 22 inflammatory/immune markers, hormone markers, tumor-related proteins, and nutrition-related variables were investigated. We also performed baseline, regression, discriminant, and receiver operating characteristic (ROC) analyses. According to NIH-Chronic Prostatitis Symptom Index (NIH-CPSI), participants were divided into chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS, pain ≥ 4; divided into IIIa and IIIb sub-groups) and non-CPPS (pain = 0; divided into IV and normal sub-groups). Analyses revealed osteocalcin as a consistent protective factor for CP/CPPS, NIH-IIIb, and NIH-IV prostatitis. Further discriminant analysis revealed that ferritin (p = 0.002) and prostate-specific antigen (PSA) (p = 0.010) were significantly associated with NIH-IIIa and NIH-IV prostatitis, respectively. Moreover, ROC analysis suggested that ferritin was the most valuable independent predictor of NIH-IIIa prostatitis (AUC = 0.639, 95% CI = 0.534-0.745, p = 0.006). Together, our study revealed inflammatory/immune markers [immunoglobulin E, Complement (C3, C4), C-reactive protein, anti-streptolysin, and rheumatoid factors], hormone markers (osteocalcin, testosterone, follicle-stimulating hormone, and insulin), tumor-related proteins (carcinoembryonic and PSA), and a nutrition-related variable (ferritin) were significantly associated with CP or one of its subtypes.

Genetic association analysis of the RTK/ERK pathway with aggressive prostate cancer highlights the potential role of CCND2 in disease progression.

The RTK/ERK signaling pathway has been implicated in prostate cancer progression. However, the genetic relevance of this pathway to aggressive prostate cancer at the SNP level remains undefined. Here we performed a SNP and gene-based association analysis of the RTK/ERK pathway with aggressive prostate cancer in a cohort comprising 956 aggressive and 347 non-aggressive cases. We identified several loci including rs3217869/CCND2 within the pathway shown to be significantly associated with aggressive prostate cancer. Our functional analysis revealed a statistically significant relationship between rs3217869 risk genotype and decreased CCND2 expression levels in a collection of 119 prostate cancer patient samples. Reduced expression of CCND2 promoted cell proliferation and its overexpression inhibited cell growth of prostate cancer. Strikingly, CCND2 downregulation was consistently observed in the advanced prostate cancer in 18 available clinical data sets with a total amount of 1,095 prostate samples. Furthermore, the lower expression levels of CCND2 markedly correlated with prostate tumor progression to high Gleason score and elevated PSA levels, and served as an independent predictor of biochemical relapse and overall survival in a large cohort of prostate cancer patients. Together, we have identified an association of genetic variants and genes in the RTK/ERK pathway with prostate cancer aggressiveness, and highlighted the potential importance of CCND2 in prostate cancer susceptibility and tumor progression to metastasis.

The feasibility of using manual segmentation in a multifeature computer-aided diagnosis system for classification of skin lesions: a retrospective comparative study.

OBJECTIVES: To investigate the feasibility of manual segmentation by users of different backgrounds in a previously developed multifeature computer-aided diagnosis (CADx) system to classify melanocytic and non-melanocytic skin lesions based on conventional digital photographic images. METHODS: In total, 347 conventional photographs of melanocytic and non-melanocytic skin lesions were retrospectively reviewed, and manually segmented by two groups of physicians, dermatologists and general practitioners, as well as by an automated segmentation software program, JSEG. The performance of CADx based on inputs from these two groups of physicians and that of the JSEG program was compared using feature agreement analysis. RESULTS: The estimated area under the receiver operating characteristic curve for classification of benign or malignant skin lesions based were comparable on individual segmentation by the gold standard (0.893, 95% CI 0.856 to 0.930), dermatologists (0.886, 95% CI 0.863 to 0.908), general practitioners (0.883, 95% CI 0.864 to 0.903) and JSEG (0.856, 95% CI 0.812 to 0.899). The agreement in the malignancy probability scores among the physicians was excellent (intraclass correlation coefficient: 0.91). By selecting an optimal cut-off value of malignancy probability score, the sensitivity and specificity were 80.07% and 81.47% for dermatologists and 79.90% and 80.20% for general practitioners. CONCLUSIONS: This study suggests that manual segmentation by general practitioners is feasible in the described CADx system for classifying benign and malignant skin lesions.

Forehead carbuncle with intractable headache.

Although carbuncles are commonly seen and may heal on their own or respond well to treatment, in rare conditions, bacteria from carbuncles can spread into the bloodstream and migrate to other areas of the body. Herein, we report on an elderly female who suffered from forehead carbuncle with intractable headache, later confirmed as having subgaleal abscess. Physicians should pay special attention to elderly and immune-compromised patients with carbuncles located on the middle of the face, especially when accompanied by intractable headache, to avoid poor outcome.

Professional continuous glucose monitoring for the identification of type 1 diabetes mellitus among subjects with insulin therapy.

The identification of type 1 diabetes in diabetic subjects receiving insulin therapy is sometimes difficult. The purpose of this study is to evaluate whether results of professional continuous glucose monitoring can improve the identification of type 1 diabetes.From 2007 to 2012, 119 adults receiving at least twice-daily insulin therapy and professional continuous glucose monitoring were recruited. Type 1 diabetes was diagnosed by endocrinologists according to American Diabetes Association standards, including a very low C-peptide level (<0.35  pg/mL) or the presence of diabetic ketoacidosis. Continuous glucose monitoring was applied for 3 days.Among 119 subjects, 86 were diagnosed with type 1 diabetes. Subjects with type 1 diabetes were younger (33.8 vs 52.3 years old, P < 0.001), had lower body mass index (BMI, 21.95 vs 24.42, P = 0.003), lower serum creatinine (61.77  vs 84.65 µmol/L, P = 0.001), and higher estimated glomerular filtration rate (108.71 vs 76.48 mg/mL/min/1.73m2, P < 0.001) than subjects with type 2 diabetes. Predictive scores for identification of type 1 diabetes were constructed, including age, BMI, average mean amplitude of glucose excursion in days 2 and 3, and the area under the curve of nocturnal hyperglycemic and hypoglycemic states. The area under the receiver operating characteristic curve was 0.90. With the cutoff of 0.58, the sensitivity was 86.7% and the specificity was 80.8%. The good performance was validated by the leave-one-out method (sensitivity 83.3%, specificity 73.1%).Professional continuous glucose monitoring is a useful tool that improves identification of type 1 diabetes among diabetic patients receiving insulin therapy.

Computer-aided diagnosis of skin lesions using conventional digital photography: a reliability and feasibility study.

BACKGROUND: Computer-aided diagnosis (CADx) software that provides a second opinion has been widely used to assist physicians with various tasks. In dermatology, however, CADx has been mostly limited to melanoma or melanocytic skin cancer diagnosis. The frequency of non-melanocytic skin cancers and the accessibility of regular digital macrographs have raised interest in developing CADx for broader applications. OBJECTIVES: To investigate the feasibility of using CADx to diagnose both melanocytic and non-melanocytic skin lesions based on conventional digital photographic images. METHODS: This study was approved by an institutional review board, and the requirement to obtain informed consent was waived. In total, 769 conventional photographs of melanocytic and non-melanocytic skin lesions were retrospectively reviewed and used to develop a CADx system. Conventional and new color-related image features were developed to classify the lesions as benign or malignant using support vector machines (SVMs). The performance of CADx was compared with that of dermatologists. RESULTS: The clinicians' overall sensitivity, specificity, and accuracy were 83.33%, 85.88%, and 85.31%, respectively. New color correlation and principal component analysis (PCA) features improved the classification ability of the baseline CADx (p = 0.001). The estimated area under the receiver operating characteristic (ROC) curve (Az) of the proposed CADx system was 0.949, with a sensitivity and specificity of 85.63% and 87.65%, respectively, and a maximum accuracy of 90.64%. CONCLUSIONS: We have developed an effective CADx system to classify both melanocytic and non-melanocytic skin lesions using conventional digital macrographs. The system's performance was similar to that of dermatologists at our institute. Through improved feature extraction and SVM analysis, we found that conventional digital macrographs were feasible for providing useful information for CADx applications. The new color-related features significantly improved CADx applications for skin cancer.