Different Effects of Propofol and Isoflurane on Cochlear Blood Flow and Hearing Function in Guinea Pigs

Objectives

To investigate the effects of isoflurane and propofol on mean arterial pressure (MAP), cochlear blood flow (CoBF), distortion-product otoacoustic emission (DPOAE), and the ultrastructure of outer hair cells (OHCs) in guinea pig cochleae.

Methods

Forty-eight male guinea pigs were randomly assigned to one of six treatment groups. Groups 1 to 3 were infused (i.v.) with a loading dose of propofol (5 mg/kg) for 5 min and three maintenance doses (10, 20, or 40 mg kg⁻¹·h⁻¹, respectively) for 115 min. Groups 4 to 6 were inhaled with isoflurane at concentrations of 1.15 vol%, 2.30 vol% or 3.45 vol% respectively for 120 min. CoBF and MAP were recorded prior to and at 5 min intervals during drug administration. DPOAE was measured before, immediately after, and 1 h after administration. Following the final DPOAE test, cochleae were examined using scanning electron microscopy.

Results

Propofol treatment reduced MAP in a dose-dependent manner. CoBF and DPOAE showed increases at propofol maintenance doses of 10 and 20 mg kg⁻¹·h⁻¹. Inhalation of isoflurane at concentrations of 2.30 vol% and 3.45 vol% reduced MAP and CoBF. DPOAE amplitude increased following inhalation of 1.15 vol% isoflurane, but decreased following inhalations of 2.30 vol% and 3.45 vol%. Cochlear structure was changed following inhalation of either 2.30 vol% or 3.45 vol% isoflurane.

Conclusions

Propofol could decrease MAP and increase both CoBF and DPOAE without affecting OHC structure. Inhalation of isoflurane at concentrations >2.30 vol% decreased CoBF and DPOAE, and produced injury to OHCs.     

99mTc-3P4-RGD2 Scintimammography in the Assessment of Breast Lesions: Comparative Study with 99mTc-MIBI

Purpose

To compare the potential application of ^99mTc-3P-Arg-Gly-Asp (^99mTc-3P₄-RGD₂) scintimammography (SMM) and ^99mTc-methoxyisobutylisonitrile (^99mTc-MIBI) SMM for the differentiation of malignant from benign breast lesions.

Method

Thirty-six patients with breast masses on physical examination and/or suspicious mammography results that required fine needle aspiration cytology biopsy (FNAB) were included in the study. ^99mTc-3P₄-RGD₂ and ^99mTc-MIBI SMM were performed with single photon emission computed tomography (SPECT) at 60 min and 20 min respectively after intravenous injection of 738±86 MBq radiotracers on a separate day. Images were evaluated by the tumor to non-tumor localization ratios (T/NT). Receiver operating characteristic (ROC) curve analysis was performed on each radiotracer to calculate the cut-off values of quantitative indices and to compare the diagnostic performance for the ability to differentiate malignant from benign diseases.

Results

The mean T/NT ratio of ^99mTc-3P₄-RGD₂ in malignant lesions was significantly higher than that in benign lesions (3.54±1.51 vs. 1.83±0.98, p<0.001). The sensitivity, specificity, and accuracy of ^99mTc-3P₄-RGD₂ SMM were 89.3%, 90.9% and 89.7%, respectively, with a T/NT cut-off value of 2.40. The mean T/NT ratio of ^99mTc-MIBI in malignant lesions was also significantly higher than that in benign lesions (2.86±0.99 vs. 1.51±0.61, p<0.001). The sensitivity, specificity and accuracy of ^99mTc-MIBI SMM were 87.5%, 72.7% and 82.1%, respectively, with a T/NT cut-off value of 1.45. According to the ROC analysis, the area under the curve for ^99mTc-3P₄-RGD₂ SMM (area = 0.851) was higher than that for ^99mTc-MIBI SMM (area = 0.781), but the statistical difference was not significant.

Conclusion

^99mTc-3P₄-RGD₂ SMM does not provide any significant advantage over the established ^99mTc-MIBI SMM for the detection of primary breast cancer. The T/NT ratio of ^99mTc-3P₄-RGD₂ SMM was significantly higher than that of ^99mTc-MIBI SMM. Both tracers could offer an alternative method for elucidating non-diagnostic mammograms.     

Altered Resting-State Amygdala Functional Connectivity after 36 Hours of Total Sleep Deprivation

Objectives

Recent neuroimaging studies have identified a potentially critical role of the amygdala in disrupted emotion neurocircuitry in individuals after total sleep deprivation (TSD). However, connectivity between the amygdala and cerebral cortex due to TSD remains to be elucidated. In this study, we used resting-state functional MRI (fMRI) to investigate the functional connectivity changes of the basolateral amygdala (BLA) and centromedial amygdala (CMA) in the brain after 36 h of TSD.

Materials and Methods

Fourteen healthy adult men aged 25.9±2.3 years (range, 18–28 years) were enrolled in a within-subject crossover study. Using the BLA and CMA as separate seed regions, we examined resting-state functional connectivity with fMRI during rested wakefulness (RW) and after 36 h of TSD.

Results

TSD resulted in a significant decrease in the functional connectivity between the BLA and several executive control regions (left dorsolateral prefrontal cortex [DLPFC], right dorsal anterior cingulate cortex [ACC], right inferior frontal gyrus [IFG]). Increased functional connectivity was found between the BLA and areas including the left posterior cingulate cortex/precuneus (PCC/PrCu) and right parahippocampal gyrus. With regard to CMA, increased functional connectivity was observed with the rostral anterior cingulate cortex (rACC) and right precentral gyrus.

Conclusion

These findings demonstrate that disturbance in amygdala related circuits may contribute to TSD psychophysiology and suggest that functional connectivity studies of the amygdala during the resting state may be used to discern aberrant patterns of coupling within these circuits after TSD.     

Angelica Sinensis Polysaccharides Stimulated UDP-Sugar Synthase Genes through Promoting Gene Expression of IGF-1 and IGF1R in Chondrocytes: Promoting Anti-Osteoarthritic Activity

Background

Osteoarthritis (OA) is a chronic joints disease characterized by progressive degeneration of articular cartilage due to the loss of cartilage matrix. Previously, we found, for the first time, that an acidic glycan from Angelica Sinensis Polysaccharides (APSs), namely the APS-3c, could protect rat cartilage from OA due to promoting glycosaminoglycan (GAG) synthesis in chondrocytes. In the present work, we tried to further the understanding of ASP-3c’s anti-OA activity.

Methodology/Principal Findings

Human primary chondrocytes were treated with APS-3c or/and recombinant human interleukin 1β (IL-1β). It turned out that APS-3c promoted synthesis of UDP-xylose and GAG, as well as the gene expression of UDP-sugar synthases (USSs), insulin like growth factor 1 (IGF1) and IGF1 receptor (IGF1R), and attenuated the degenerative phenotypes, suppressed biosynthesis of UDP-sugars and GAG, and inhibited the gene expression of USSs, IGF1 and IGF1R induced by IL-1β. Then, we induced a rat OA model with papain, and found that APS-3c also stimulated GAG synthesis and gene expression of USSs, IGF1 and IGF1R in vivo. Additionally, recombinant human IGF1 and IGF1R inhibitor NP-AEW541 were applied to figure out the correlation between stimulated gene expression of USSs, IGF1 and IGF1R induced by APS-3c. It tuned out that the promoted GAG synthesis and USSs gene expression induced by APS-3c was mediated by the stimulated IGF1 and IGF1R gene expression, but not through directly activation of IGF1R signaling pathway.

Conclusions/Significances

We demonstrated for the first time that APS-3c presented anti-OA activity through stimulating IGF-1 and IGF1R gene expression, but not directly activating the IGF1R signaling pathway, which consequently promoted UDP-sugars and GAG synthesis due to up-regulating gene expression of USSs. Our findings presented a better understanding of APS-3c’s anti-OA activity and suggested that APS-3c could potentially be a novel therapeutic agent for OA.     

Time-Varying Pattern of Postoperative Recurrence Risk of Early-Stage (T1a-T2bN0M0) Non-Small Cell Lung Cancer (NSCLC): Results of a Single-Center Study of 994 Chinese Patients

Background

The aim of this study was to analyze the time-varying pattern of recurrence risk of early-stage (T1a-T2bN0M0) non-small cell lung cancer (NSCLC) after surgery using the hazard function and identify patients who might benefit from adjuvant chemotherapy.

Patients and Methods

This retrospective study enrolled 994 patients with early-stage NSCLC who underwent radical surgical resection between January 1999 and October 2009. Survival curves were generated using the Kaplan-Meier method, and the annual recurrence hazard was estimated using the hazard function.

Results

The median recurrence-free survival (RFS) was 8.8 years. The life table survival analysis showed that the 1-year, 3-year, 5-year and 10-year recurrence rates were 82.0%, 67.0%, 59.0% and 48.0%, respectively. Approximately 256 (25.7%) patients experienced relapse [locoregional: 32 (3.2%) and distant: 224 (22.5%)], and 162 patients died from cancer. The annual recurrence hazard curve for the entire population showed that the first major recurrence surge reached a maximum 1.6 years after surgery. The curve subsequently declined until reaching a nadir at 7.2 years. A second peak occurred at 8.8 years. An analysis of clinical-pathological factors demonstrated that this double-peaked pattern was present in several subgroups.

Conclusions

The presence of a double-peaked pattern indicates that there is a predictable temporal distribution of the recurrence hazard of early-stage NSCLC. The annual recurrence hazard may be an effective method of selecting patients at high risk of recurrence, who may benefit from adjuvant therapy.     

Toll-Like Receptor 4 Prompts Human Breast Cancer Cells Invasiveness via Lipopolysaccharide Stimulation and Is Overexpressed in Patients with Lymph Node Metastasis

Toll-like receptor (TLR)4-mediated signaling has been implicated in tumor cell invasion, survival, and metastasis in a variety of cancers. This study investigated the expression and biological role of TLR4 in human breast cancer metastasis. MCF-7 and MDA-MB-231 are human breast cancer cell lines with low and high metastatic potential, respectively. Using lipopolysaccharide (LPS) to stimulate MCF-7 and MDA-MB-231 cells, expression of TLR4 mRNA and protein increased compared with that in control cells. TLR4 activation notably up-regulated expression of matrix metalloproteinase (MMP)-2, MMP-9 and vascular endothelial growth factor(VEGF) mRNA and their secretion in the supernatants of both cell lines. LPS enhanced invasion of MDA-MB-231 cells by transwell assay and MCF-7 cells by wound healing assay. LPS triggered increased expression of TLR4 downstream signaling pathway protein myeloid differentiation factor 88(MyD88) and resulted in interleukin (IL)-6 and IL-10 higher production by human breast cancer cells. Stimulation of TLR4 with LPS promoted tumorigenesis and formed metastatic lesions in liver of nude mice. Moreover, expression of TLR4 and MyD88 as well as invasiveness and migration of the cells could be blocked by TLR4 antagonist. Combined with clinicopathological parameters, TLR4 was overexpressed in human breast cancer tissue and correlated with lymph node metastasis. These findings indicated that TLR4 may participate in the progression and metastasis of human breast cancer and provide a new therapeutic target.     

Conserved Dopamine Neurotrophic Factor-Transduced Mesenchymal Stem Cells Promote Axon Regeneration and Functional Recovery of Injured Sciatic Nerve

Peripheral nerve injury (PNI) is a common disease that often results in axonal degeneration and the loss of neurons, ultimately leading to limited nerve regeneration and severe functional impairment. Currently, there are no effective treatments for PNI. In the present study, we transduced conserved dopamine neurotrophic factor (CDNF) into mesenchymal stem cells (MSCs) in collagen tubes to investigate their regenerative effects on rat peripheral nerves in an in vivo transection model. Scanning electron microscopy of the collagen tubes demonstrated their ability to be resorbed in vivo. We observed notable overexpression of the CDNF protein in the distal sciatic nerve after application of CDNF-MSCs. Quantitative analysis of neurofilament 200 (NF200) and S100 immunohistochemistry showed significant enhancement of axonal and Schwann cell regeneration in the group receiving CDNF-MSCs (CDNF-MSCs group) compared with the control groups. Myelination thickness, axon diameter and the axon-to fiber diameter ratio (G-ratio) were significantly higher in the CDNF-MSCs group at 8 and 12 weeks after nerve transection surgery. After surgery, the sciatic functional index, target muscle weight, wet weight ratio of gastrocnemius muscle and horseradish peroxidase (HRP) tracing demonstrated functional recovery. Light and electron microscopy confirmed successful regeneration of the sciatic nerve. The greater numbers of HRP-labeled neuron cell bodies and increased sciatic nerve index values (SFI) in the CDNF-MSCs group suggest that CDNF exerts neuroprotective effects in vivo. We also observed higher target muscle weights and a significant improvement in muscle atrophism in the CDNF-MSCs group. Collectively, these findings indicate that CDNF gene therapy delivered by MSCs is capable of promoting nerve regeneration and functional recovery, likely because of the significant neuroprotective and neurotrophic effects of CDNF and the superior environment offered by MSCs and collagen tubes.     

HIF-1α Signaling Activation by Post-Ischemia Treatment with Astragaloside IV Attenuates Myocardial Ischemia-Reperfusion Injury

In this study, we evaluated the effect of astragaloside IV (Ast IV) post-ischemia treatment on myocardial ischemia-reperfusion (IR) injury (IRI). We also examined whether hypoxia inducible factor-1α (HIF-1α) and its downstream gene-inducible nitric oxide (NO) synthase (iNOS) play roles in the cardioprotective effect of Ast IV. Cultured cardiomyocytes and perfused isolated rat hearts were exposed to Ast IV during reperfusion in the presence or absence of the HIF-1α inhibitor 2-methoxyestradiol (2-MeOE2). The post-ischemia treatment with Ast IV protected cardiomyocytes from the apoptosis and death induced by simulated IRI (SIRI). Additionally, in cardiomyocytes, 2-MeOE2 and HIF-1α siRNA treatment each not only abolished the anti-apoptotic effect of post-ischemia treatment with Ast IV but also reversed the upregulation of HIF-1α and iNOS expression. Furthermore, after treatment with Ast IV, post-ischemic cardiac functional recovery and lactate dehydrogenase (LDH) release in the coronary flow (CF) were improved, and the myocardial infarct size was decreased. Moreover, the number of apoptotic cells was reduced, and the upregulation of the anti-apoptotic protein Bcl2 and downregulation of the pro-apoptotic protein Caspase3 were reversed. 2-MeOE2 reversed these effects of Ast IV on IR-injured hearts. These results suggest that post-ischemia treatment with Ast IV can attenuate IRI by upregulating HIF-1α expression, which transmits a survival signal to the myocardium.     

Oncogenic GNAQ and GNA11 Mutations in Uveal Melanoma in Chinese

Purpose

To examine whether GNAQ and GNA11 somatic mutations previously identified in uveal melanomas of Caucasians are associated with uveal melanomas in Chinese patients.

Methods

Uveal melanomas treated by primary enucleation in Chinese patients underwent a mutation analysis of GNAQ and GNA11 with sequencing of exon 5 and exon 4.

Results

The study included 50 patients with uveal melanoma and with a mean age of 47.6±13.0 years. During the follow-up of at least 3 years, 20 (40%) patients developed extraocular metastases. The frequencies of GNAQ and GNA11 somatic mutations in uveal melanoma were 18% (9/50) and 20% (10/50), respectively. The mutations occurred exclusively in codon 209 of exon 5. No mutations were detected in exon 4. Mutations affecting codon 209 in GNAQ were c.626A>C(Q209P) (78%) and c.626A>T(Q209L) (22%). Mutations affecting codon 209 in GNA11 were exclusively c.626A>T(Q209L) (100%). In none of the tumors, mutations of BRAF and NRAS were detected. GNAQ/11 mutations were marginally (P = 0.045) associated with optic disc involvement. In Kaplan-Meier analysis, metastasis-free survival was not significantly (P = 0.94) associated with GNAQ/11 mutations.

Conclusions

Mutations of GNAQ and GNA11 can be found in Chinese patients as in Caucasian patients with uveal melanoma, with a higher frequency reported for Caucasian patients.