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Neuronal loss is a hallmark of stroke and other neurodegenerative diseases, and as such, neuronal loss caused by microglia has been thought to be a contributing factor to disease progression. Here, we show that microglia indeed contribute significantly to neuronal loss in a mouse model of stroke, but this microglial-dependent process of neuronal clearance specifically targets stressed and degenerating neurons in the ischemic cortical region and not healthy non-ischemic neurons. Nonspecific stimulation of microglia decreased the density of neurons in the ischemic cortical region, whereas specific inhibition of MFG-E8 signaling, which is required for microglial phagocytosis of neurons, had the opposite effect. In both scenarios, the effects were microglia specific, as the same treatments had no effect in mice whose microglia were depleted prior to stroke. Finally, even though the inhibition of MFG-E8 signaling increased neuronal density in the ischemic brain region, it substantially exacerbated the development of cortical infarction. In conclusion, microglia through MFG-E8 signaling contribute to the loss of ischemic neurons and, in doing so, minimize the development of cortical infarction after stroke. [ABSTRACT FROM AUTHOR]

Proper placement of suture anchors is an important step in Bankart repair as improper placement can lead to failure. Concern surrounding suture anchor placement inspired the use navigation systems in shoulder arthroscopy. We aimed to demonstrate the technological advantage of using the O-arm (Medtronic Navigation, Denver, CO, USA) image guidance system to provide real-time images during portal and anchor placements in shoulder arthroscopy. Consecutive patients (from July to October 2014) who were admitted for arthroscopic capsulolabral repair surgeries were included. Ten patients were randomly enrolled in the navigation group and 10 in the traditional group. The glenoid was divided into four zones, and the penetration rates in each zone were compared between the two groups. In zone III, the most inferior region of the glenoid, the penetration rate was 40.9% in the traditional group and 15.7% in the navigation group (P = 0.077), demonstrating a trend toward improved accuracy of anchor placement with the aid of the navigation system; however, this was not statistically significant. Average surgical time in the navigation and traditional groups was 177.6±40.2 and 117.7±17.6 mins, respectively. American Shoulder and Elbow Surgeons Shoulder Scores showed no difference before and 6 months after surgery. This pilot study showed a trend toward decreased penetration rate in O-arm-navigated capsulolabral repair surgeries and decreased risks of implant misplacement; however, possibly due to the small sample size, the difference was not statistically significant. Further large-scale studies are needed to confirm the possible benefit of the navigation system. Even with the use of navigation systems, there were still some penetrations in zone III of the glenoid. This penetration may be attributed to the micro-motion of the acromioclavicular joint. Although the navigation group showed a significant increase in surgical time, with improvements in instrument design, O-arm-navigated arthroscopy will gain popularity in clinical practice. [ABSTRACT FROM AUTHOR]

Excitotoxicity mediated by the N-methyl-D-aspartate receptor (NMDAR) is believed to be a primary mechanism of neuronal injury following stroke. Thus, many drugs and therapeutic peptides were developed to inhibit either the NMDAR at the cell surface or its downstream intracellular death-signaling cascades. Nevertheless, the majority of focal ischemia studies concerning NMDAR antagonism were performed using the intraluminal suture-induced middle cerebral arterial occlusion (MCAO) model, which produces a large cortical and subcortical infarct leading to hypothalamic damage and fever in experimental animals. Here, we investigated whether NMDAR antagonism by drugs and therapeutic peptides was neuroprotective in a mouse model of distal MCAO (dMCAO), which produces a small cortical infarct sparing the hypothalamus and other subcortical structures. For establishment of this model, mice were subjected to dMCAO under normothermic conditions or body-temperature manipulations, and in the former case, their brains were collected at 3–72 h post-ischemia to follow the infarct development. These mice developed cortical infarction 6 h post-ischemia, which matured by 24–48 h post-ischemia. Consistent with the hypothesis that the delayed infarction in this model can be alleviated by neuroprotective interventions, hypothermia strongly protected the mouse brain against cerebral infarction in this model. To evaluate the therapeutic efficacy of NMDAR antagonism in this model, we treated the mice with MK801, Tat-NR2B9c, and L-JNKI-1 at doses that were neuroprotective in the MCAO model, and 30 min later, they were subjected to 120 min of dMCAO either in the awake state or under anesthesia with normothermic controls. Nevertheless, NMDAR antagonism, despite exerting pharmacological effects on mouse behavior, repeatedly failed to show neuroprotection against cerebral infarction in this model. The lack of efficacy of these treatments is reminiscent of the recurrent failure of NMDAR antagonism in clinical trials. While our data do not exclude the possibility that these treatments could be effective at a different dose or treatment regimen, they emphasize the need to test drug efficacy in different stroke models before optimal doses and treatment regimens can be selected for clinical trials. [ABSTRACT FROM AUTHOR]

Introduction: The signal characteristics of intracardiac bipolar electrograms at the origin of idiopathic RVOT-VT during sinus rhythm remain unclear. Objective: The study sought to develop a novel real-time/online technique, simultaneous amplitude frequency electrogram transformation (SAFE-T), to quantify and localize the diseased ventricular substrate in idiopathic RVOT-VT. Methods: We retrospectively investigated the intracardiac bipolar recordings in 70 consecutive patients (26% male, mean age 42±12 years) who underwent successful radiofrequency catheter ablation of idiopathic RVOT-VT. We quantified the extent of the frequency fraction of ventricular potentials during sinus rhythm or ventricular pacing using a novel formula, the product of instantaneous amplitude and frequency, and showed that in a 3D geometry as an online SAFE-T map. Results: The characteristics of the HHT spectra of electrograms derived from VT origins demonstrated high frequency components (>70 Hz), which were independent of the rhythm. The density of the abnormal potentials at the VT origins were higher (VT origins, 7.5±2.3 sites/cm2 vs. surrounding myocardium, 1.5±1.3 sites/cm2, p<0.001), and were significantly decreased after ablation (0.7±0.6 sites/cm2, p<0.001). A small region of abnormal potentials were observed in the VT origins (mean area of 1.5±0.8 cm2). The SAFE-T maps predicted the VT origins with 92% sensitivity, 78% specificity with optimal cut-off value of >3.0 Hz·mV. Conclusion: The online SAFE-T map was feasible for quantifying the diseased ventricular substrate, irrespective of the rhythm of activation, and can be used to identify the optimal ablation targets for idiopathic RVOT-VT. We found a limited region of abnormal potentials where the RVOT-VT origins were successfully ablated. [ABSTRACT FROM AUTHOR]

Purpose: To assess wavefront derived refraction and full eye biometry including ciliary muscle dimension and full eye axial geometry in pseudophakic eyes using spectral domain OCT equipped with a Shack-Hartmann wavefront sensor. Methods: Twenty-eight adult subjects (32 pseudophakic eyes) having recently undergone cataract surgery were enrolled in this study. A custom system combining two optical coherence tomography systems with a Shack-Hartmann wavefront sensor was constructed to image and monitor changes in whole eye biometry, the ciliary muscle and ocular aberration in the pseudophakic eye. A Badal optical channel and a visual target aligning with the wavefront sensor were incorporated into the system for measuring the wavefront-derived refraction. The imaging acquisition was performed twice. The coefficients of repeatability (CoR) and intraclass correlation coefficient (ICC) were calculated. Results: Images were acquired and processed successfully in all patients. No significant difference was detected between repeated measurements of ciliary muscle dimension, full-eye biometry or defocus aberration. The CoR of full-eye biometry ranged from 0.36% to 3.04% and the ICC ranged from 0.981 to 0.999. The CoR for ciliary muscle dimensions ranged from 12.2% to 41.6% and the ICC ranged from 0.767 to 0.919. The defocus aberrations of the two measurements were 0.443 ± 0.534 D and 0.447 ± 0.586 D and the ICC was 0.951. Conclusions: The combined system is capable of measuring full eye biometry and refraction with good repeatability. The system is suitable for future investigation of pseudoaccommodation in the pseudophakic eye. [ABSTRACT FROM AUTHOR]

Enterovirus 71 (EV71) is a neurotropic virus capable of inducing severe neurological symptoms and death. No direct targeting antivirals are useful in the treatment of severe EV71 infection. Because of low toxicity and good specificity, monoclonal antibodies (MAb) are a potential candidate for the treatment of viral infections. Therefore, we developed an EV71-specific conformational MAb with high in vitro cross-neutralization activity to heterologous EV71 subgenotypes. The in vivo treatment experiment at different days post-infection indicated that a single treatment of MAb CT11F9 within day 3 post-infection fully protected mice from morbidity and mortality (0% PBS vs. 100% at 10 µg/g per body weight ***P<0.0001). Immunohistochemical and histological analysis confirmed that CT11F9 significantly prohibited EV71 VP1 expression in various tissues and prevented EV71-induced myonecrosis. Moreover, thrice-treatment at day 4, 5, 6 post-infection was associated with an increased survival rate (18.2% single vs. 50% thrice at 20 µg/g per body weight), and the mice recovered from limb paralysis. Competitive ELISA also confirmed that CT11F9-recognized epitopes were immunodominant in humans. In conclusion, MAb CT11F9 is an ideal candidate to be humanized and used in severe EV71 infection. [ABSTRACT FROM AUTHOR]

Glioblastoma (GBM) is the most common primary brain tumor in adults. The poor prognosis and minimally successful treatments of these tumors indicates a need to identify new therapeutic targets. Therapy resistance of GBMs is attributed to heterogeneity of the glioblastoma due to genetic alterations and functional subpopulations. Chemokine receptors CXCR4 and CXCR7 play important roles in progression of various cancers although the specific functions of the CXCL12−CXCR4−CXCR7 axis in GBM are less characterized. In this study we examined the expression and function of CXCR4 and CXCR7 in four primary patient-derived GBM cell lines of the proliferative subclass, investigating their roles in in vitro growth, migration, sphere and tube formation. CXCR4 and CXCR7 cell surface expression was heterogeneous both between and within each cell line examined, which was not reflected by RT-PCR analysis. Variable percentages of CXCR4+CXCR7− (CXCR4 single positive), CXCR4−CXCR7+ (CXCR7 single positive), CXCR4+CXCR7+ (double positive), and CXCR4−CXCR7− (double negative) subpopulations were evident across the lines examined. A subpopulation of slow cell cycling cells was enriched in CXCR4 and CXCR7. CXCR4+, CXCR7+, and CXCR4+/CXCR7+ subpopulations were able to initiate intracranial tumors in vivo. CXCL12 stimulated in vitro cell growth, migration, sphere formation and tube formation in some lines and, depending on the response, the effects were mediated by either CXCR4 or CXCR7. Collectively, our results indicate a high level of heterogeneity in both the surface expression and functions of CXCR4 and CXCR7 in primary human GBM cells of the proliferative subclass. Should targeting of CXCR4 and CXCR7 provide clinical benefits to GBM patients, a personalized treatment approach should be considered given the differential expression and functions of these receptors in GBM. [ABSTRACT FROM AUTHOR]

Cancer cells respond to stress by activating a variety of survival signaling pathways. A disintegrin and metalloproteinase (ADAM) 9 is upregulated during cancer progression and hormone therapy, functioning in part through an increase in reactive oxygen species. Here, we present in vitro and in vivo evidence that therapeutic targeting of ADAM9 gene expression by lentivirus-delivered small hairpin RNA (shRNA) significantly inhibited proliferation of human prostate cancer cell lines and blocked tumor growth in a murine model of prostate cancer bone metastasis. Cell cycle studies confirmed an increase in the G1-phase and decrease in the S-phase population of cancer cells under starvation stress conditions, which correlated with elevated intracellular superoxide levels. Microarray data showed significantly decreased levels of regenerating islet-derived family member 4 (REG4) expression in prostate cancer cells with knockdown of ADAM9 gene expression. This REG4 downregulation also resulted in induction of expression of p21(Cip1/WAF1), which negatively regulates cyclin D1 and blocks the G1/S transition. Our data reveal a novel molecular mechanism of ADAM9 in the regulation of prostate cancer cell proliferation, and suggests a combined modality of ADAM9 shRNA gene therapy and cytotoxic agents for hormone refractory and bone metastatic prostate cancer.