The feasibility of SHIMP for judging subjective vertigo and recovery in patients with vestibular neuritis.

PURPOSE: We aimed to study the results of the head impulse paradigm (HIMP) and the suppression head impulse paradigm (SHIMP) in patients with acute vestibular neuritis (AVN) to compare dizziness handicap inventory (DHI) scores before and after treatment. We also wanted to investigate the correlation between the HIMP, SHIMP and DHI score and to analyze the factors that affect the recovery with AVN in the short term. METHODS: The HIMP, SHIMP, and DHI score were assessed in 20 patients with AVN before (T0) and after treatment (T1). We collected the following indicators: T0, T1-HIMP VOR gain; T0, T1-SHIMP VOR gain; the percentage of the anti-compensatory saccades of T0-SHIMP and T1-SHIMP on the affected side; T0-DHI score, T1-DHI score; and efficacy index (EI). The correlation between HIMP and SHIMP parameters with the DHI score and EI was analyzed, and the factors that affect the recovery of patients with AVN were assessed. RESULTS: T0-SHIMP anti-compensatory saccades (%),T1-SHIMP VOR gain, and T1-SHIMP anti-compensatory saccades (%) were significantly correlated with the corresponding DHI score and EI (P < 0.05). T0, T1-HIMP VOR gain and T0-SHIMP VOR gain had no correlation with the corresponding DHI score and EI (P > 0.05). T0-SHIMP anti-compensatory saccades (%) significantly affect EI (P < 0.05). CONCLUSION: Both HIMP and SHIMP can assess the current vestibular function and recovery of AVN patients, but SHIMP can more accurately reflect the degree of subjective vertigo. At the same time, T0-SHIMP anti-compensatory saccades (%) can be used as a good index to evaluate the short-term recovery of AVN patients.

Nitazoxanide, an Antiprotozoal Drug, Reduces Bone Loss in Ovariectomized Mice by Inhibition of RANKL-Induced Osteoclastogenesis.

Nitazoxanide (NTZ) is an FDA-approved anti-parasitic drug with broad-spectrum anti-infective, anti-inflammatory, and antineoplastic potential. However, its regulatory effects on osteoclastogenesis and the underlying mechanisms remain unclear. The present study found that NTZ potently inhibited osteoclast formation at the early stage of receptor activator of NF-κB ligand-induced osteoclastogenesis in a concentration-dependent manner at a non-growth inhibitory concentration. NTZ suppressed actin ring formation and decreased osteoclast marker gene expression, including TRAP, MMP9, and cathepsin K. NTZ significantly impaired the bone resorption activity of osteoclasts. In vivo, ovariectomized mice were treated with 50, 100 and 200 mg/kg/d NTZ for 3 months. NTZ (100 mg/kg/d) administration markedly reduced ovariectomy-induced bone loss by suppressing osteoclast activity. Mechanistically, osteoclastogenesis blockade elicited by NTZ resulted from inhibition of STAT3 phosphorylation, and reduction of the Ca2+ fluorescence intensity and NFATc1 expression. NTZ weakened the binding between STAT3 and the NFATc1 promoter region. Furthermore, enforced NFATc1 expression partly rescued the impaired osteoclast differentiation in NTZ-treated RAW264.7 cells. In summary, NTZ could inhibit osteoclastogenesis and bone loss through modulation of the receptor activator of NF-κB ligand-induced STAT3-NFATc1 signaling pathway, which might be a potential alternative treatment regimen against bone destruction-related diseases including osteoporosis.

Clinical implementation of plasma EGFR T790M testing using droplet digital PCR in TKI-resistant NSCLC patients.

BACKGROUND: Majority of non-small cell lung cancer (NSCLC) patients progressed on epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) due to acquired T790M mutation. Blood sample is increasingly used in clinical setting for EGFR T790M detection and our laboratory employed the droplet digital PCR (ddPCR) methodology for testing. This study investigated the positive rate, specimen type for rebiopsy and clinical impact of blood-based EGFR T790M testing. METHODS: We retrospectively evaluated clinical samples that underwent plasma EGFR T790M testing in TTSH Molecular Diagnostic Laboratory from August 2017 to September 2019. Data on diagnosis, EGFR activating and T790M mutations, and treatment strategies were recorded. RESULTS: A total of 104 progressive NSCLC cases were included in this study. Overall, 46 patients (44.2%) were tested T790M positive, and 47.8% of these tested positive had low levels (defined as ≤3% fractional abundance and <50 copies/mL plasma), which may be missed by the conventional methods with lower sensitivity. Of these tested with low T790M abundance, 77.3% subsequently received osimertinib. Activating mutations were not detected in 42 (40.4%) cases, indicating that the tumors were not actively shedding ctDNA. Among these, 24 patients underwent repeat testing with tissue or blood specimens. Thirteen patients were subsequently tested T790M positive and 12 of them switched treatment to osimertinib. The recommendation to repeat testing with a different biopsy or after a suitable interval increased the overall positive rate to 56.7% (59/104). CONCLUSION: The use of a highly sensitive platform such as ddPCR for the detection of low abundance T790M, and the approach of repeat testing in cases with insufficient ctDNA increased the positive rate. This in turn identified more patients who are eligible for targeted therapy.

miR-140-3p exhibits repressive functions on preosteoblast viability and differentiation by downregulating MCF2L in osteoporosis.

Previous research manifested that miR-140-3p was a latent biomarker for osteoporosis. Nevertheless, the mechanism of miR-140-3p in osteoporosis is still not clear and needs ulteriorly studying. The purpose of our paper was to ulteriorly probe the underlying mechanism of miR-140-3p on osteoporosis. Firstly, based on the data acquired from GEO database, we found that miR-140-3p was highly expressed; meanwhile, MCF2L was lowly expressed in osteoporosis patients. Upregulation/downregulation of miR-140-3p by miR-140-3p mimic/inhibitor restrained/promoted MC3T3-E1 cell viability and differentiation. However, miR-140-3p over-expression/downregulation accelerated/repressed MC3T3-E1 cell apoptosis. MCF2L was forecasted as a target of miR-140-3p by miRanda, miRWalk, and TargetScan miRNA target gene prediction software. Luciferase reporter assay confirmed that MCF2L could be directly targeted by miR-140-3p. Moreover, we identified that the expression of MCF2L was negatively regulated by miR-140-3p. From rescue assays, we discovered that knockdown of MCF2L weakened the promoting influence of miR-140-3p ablation on MC3T3-E1 cell viability and differentiation, and receded the suppressing impact of miR-140-3p reduction on MC3T3-E1 cell apoptosis. Above all, this research disclosed that miR-140-3p repressed preosteoblast viability and differentiation while promoted preosteoblast apoptosis via targeting MCF2L. Our discoveries might afford a theoretical basis of developing a latent novel target for osteoporosis therapy.

Cervical kyphosis in asymptomatic populations: incidence, risk factors, and its relationship with health-related quality of life.

BACKGROUND: Cervical kyphosis has been pointed out in asymptomatic populations. The purposes of this study were (1) to investigate the incidence of cervical kyphosis in asymptomatic populations, (2) to identify risk factors related to cervical kyphosis, and (3) to assess the relationship between cervical kyphosis and health-related quality of life (HRQOL). METHODS: A cohort of 235 asymptomatic volunteers' records was retrospectively analyzed. Radiographic parameters of the coronal and sagittal planes were measured in the full-length spine x-ray. All patients were classified into two groups based on the cervical lordosis angle: cervical lordosis (CL) and cervical kyphosis (CK). HRQOL was evaluated by EQ-5D and SF-36 (PCS and MCS) questionnaires. RESULTS: CK was observed in 90 of 235 (38.3%) participants. There was a significant difference with regard to age between volunteers with CK and CL (32.23 ± 8.12 vs. 42.12 ± 6.14, p < 0.05). Several parameters had a significant relationship with CK, including TK, T1 slope, TIA, SVA, and CT. Logistic regression analysis identified age, TK, T1 slope, and SVA as independent risk factors of CK. In addition, there was a negative correlation between CK and the parameters of HRQOL (EQ-5D, - 0.63; PCS, - 0.68; MCS, - 0.59). CONCLUSIONS: The incidence of CK in normal populations is 38.3%. Some spinal parameters are related to CK. CK is associated with the HRQOL.

Mammalian Target of Rapamycin Complex 1 Signaling Is Required for the Dedifferentiation From Biliary Cell to Bipotential Progenitor Cell in Zebrafish Liver Regeneration.

The liver has a high regenerative capacity. Upon two-thirds partial hepatectomy, the hepatocytes proliferate and contribute to liver regeneration. After severe liver injury, when the proliferation of residual hepatocytes is blocked, the biliary epithelial cells (BECs) lose their morphology and express hepatoblast and endoderm markers, dedifferentiate into bipotential progenitor cells (BP-PCs), then proliferate and redifferentiate into mature hepatocytes. Little is known about the mechanisms involved in the formation of BP-PCs after extreme liver injury. Using a zebrafish liver extreme injury model, we found that mammalian target of rapamycin complex 1 (mTORC1) signaling regulated dedifferentiation of BECs and proliferation of BP-PCs. mTORC1 signaling was up-regulated in BECs during extreme hepatocyte ablation and continuously expressed in later liver regeneration. Inhibition of mTORC1 by early chemical treatment before hepatocyte ablation blocked the dedifferentiation from BECs into BP-PCs. Late mTORC1 inhibition after liver injury reduced the proliferation of BP-PC-derived hepatocytes and BECs but did not affect BP-PC redifferentiation. mTOR and raptor mutants exhibited defects in BEC transdifferentiation including dedifferentiation, BP-PC proliferation, and redifferentiation, similar to the chemical inhibition. Conclusion: mTORC1 signaling governs BEC-driven liver regeneration by regulating the dedifferentiation of BECs and the proliferation of BP-PC-derived hepatocytes and BECs.

Knockdown of UBE2T Inhibits Osteosarcoma Cell Proliferation, Migration, and Invasion by Suppressing the PI3K/Akt Signaling Pathway.

Ubiquitin-conjugating enzyme E2T (UBE2T), a member of the E2 family, was found to be overexpressed in a great many cancers such as bladder cancer, lung cancer, and prostate cancer. However, there have been no reports on the role of UBE2T in osteosarcoma. In this study, we tried to make the effects of UBE2T on osteosarcoma clear. The study results showed that UBE2T was overexpressed in osteosarcoma tissues and cell lines. Moreover, UBE2T knockdown inhibited osteosarcoma cell proliferation, migration, and invasion. We also observed that UBE2T downregulation could suppress the activity of the PI3K/Akt signaling pathway. Therefore, we concluded that UBE2T exerted its inhibitory effects on osteosarcoma cells via suppressing the PI3K/Akt signaling pathway. These findings indicated that UBE2T may be a potential therapeutic target for osteosarcoma treatment.

[Tuberous sclerosis complex with refractory epilepsy: a clinicopathologic study of 14 cases].

OBJECTIVE: To study the clinicopathologic features of tuberous sclerosis complex (TSC). METHODS: The clinicopathologic data of the patients diagnosed as TSC with refractory epilepsy and resection of epileptic focus were retrospectively analyzed. RESULTS: Fourteen cases were included, the mean age was (15.8±12.9) years, with a male predominance (male to female ratio=10:4). Frontal lobe was the most common (13/14) site of involvement. MRI showed multiple patchy long T1 and long T2 signals. CT images showed multiple subependymal high density calcified nodules in nine cases. Histology showed mild to severe disruption of the cortical lamination, cortical and subcortical tubers with giant cells and/or dysmorphic neurons. The giant cells showed strong immunoreactivity for vimentin and nestin, while the dysmorphic neurons partially expressed MAP2 and NF. Vimentin also stained strongly the "reactive" astrocytes. Thirteen cases had follow-up information: Engel class I in six cases, Engel class II in six cases, and Engel class III in one case. CONCLUSIONS: Diagnosis of TSC relies on combined pathologic, clinical and neuroradiological features. Immunohistochemical staining can be helpful. Resection of epileptic focus is an effective method to treat refractory epilepsy in TSC.

Lack of association between the ATP13A2 A746T variant and Parkinson's disease susceptibility in Han Chinese: a meta-analysis.

PURPOSE: To perform a meta-analysis to help resolve the controversy of whether the ATP13A2 A746T variant is associated with Parkinson's disease (PD) susceptibility in Han Chinese. METHODS: Six literature databases were searched for case-control studies published up to October 2014: Web of Science, PubMed, Embase, Chinese National Knowledge Infrastructure, Wanfang and SinoMed. RESULTS: Five eligible articles were identified, which reported six case-control studies and a total of 1703 cases and 2050 controls. The overall results suggested low frequencies of the A746T variant in Han Chinese patients (9/1703, 0.55%) and controls (6/2050, 0.29%). We failed to find evidence of significant differences in variant frequencies among Han Chinese, Uyghur and Japanese patients (p = 0.263). Analysis of pooled odds ratios (ORs) and 95% confidence interval (CIs) revealed no association between the A746T variant and overall PD risk (GA vs. GG: OR 1.78, 95%CI 0.71-4.46, p = 0.216; allele A vs. G: OR 1.90, 95%CI 0.77-4.69, p = 0.167). CONCLUSION: The ATP13A2 A746T variant is rare in Han Chinese patients and controls and is not associated with PD susceptibility in this ethnic group. Variant frequencies do not differ significantly among Han Chinese, Uyghur and Japanese patients. Further well-designed studies with larger samples are needed to validate these results.

[Research on Application of Fourier Transform Infrared Spectrometry in the Diagnosis of Lymph Node Metastasis in Gastric Cancer].

To explore the feasibility of quick intraoperative in situ and noninvasive diagnosis of lymph node metastasis in gastric cancer by Fourier transform infrared (FTIR) spectrometry. FTIR spectra of surgically removed fresh lymph nodes were measured by FTIR via probe of attenuated total reflection (ATR). For each spectrum, 13 bands were indentified and assigned between 3 000 and 1 000 cm(-1). Peaks in the spectra were measured and relative intensity ratios were calculated and compared between the spectra of Metastatic lymph nodes (MLN) and Non-metastatic lymph nodes (NMLN). Standard statistic analysis was performed. 720 lymph nodes were measured in 38 gastric cancer patients. Results show that there were significant differences between the FTIR of 540 MLN and 180 NMLN. (1) For the band related to nucleic acid: The ratios of I1240/I1460 (p = 0.015) and I1080/I1460 (p = 0.034) increased in MLN, which shows that the relative quantity of nucleic acid was more in MLN than that in NMLN. (2) For the bands related to protein: The ratios of I1640 /I1460 (p = 0.001) and I146/I1460 (p = 0.027) increased in MLN, which shows that the relative quantity of protein was more in MLN. (3) For the bands related to lipid: The ratio of I2855/I460 and I1740/I1460 decreased in MLN FTIR spectrum, indicating the lower relative quantity of lipid in MLN. (4) For the bands related to carbohydrate: The ratio of I1160/I1460 (p = 0.023) decreased in MLN FTIR spectrum, indicating the lower relative quantity of carbohydrate in MLN. The results demonstrate that the FTIR spectroscopy technique maybe develop into a promising method for in situ and quick intraoperative differential diagnosis of lymph node metastasis in gastric cancer.