Dearomative Intramolecular (4+3) Cycloadditions of Thiophenes.

Unexpectedly facile dearomative intramolecular (4+3) cycloadditions of thiophenes with epoxy enolsilanes, providing sulfur-bridged cycloadducts, are reported. A total of fifteen thiophene substrates have been found to undergo (4+3) cycloaddition smoothly to produce endo and exo (4+3) adducts in yields of up to 83 % with moderate to good diastereoselectivity. Complete conservation of enantiomeric purity was observed when the optically enriched epoxide was used. The desulfurizing transformations of the sulfur-bridged skeleton of the cycloadducts provide functionalized 6,7-fused bicyclic frameworks consisting of 1,3-cycloheptadiene subunits. Density functional theory calculations reveal the origins of the facile dearomatization of thiophenes in these (4+3) cycloadditions.

Intelligent surgical workflow recognition for endoscopic submucosal dissection with real-time animal study.

Recent advancements in artificial intelligence have witnessed human-level performance; however, AI-enabled cognitive assistance for therapeutic procedures has not been fully explored nor pre-clinically validated. Here we propose AI-Endo, an intelligent surgical workflow recognition suit, for endoscopic submucosal dissection (ESD). Our AI-Endo is trained on high-quality ESD cases from an expert endoscopist, covering a decade time expansion and consisting of 201,026 labeled frames. The learned model demonstrates outstanding performance on validation data, including cases from relatively junior endoscopists with various skill levels, procedures conducted with different endoscopy systems and therapeutic skills, and cohorts from international multi-centers. Furthermore, we integrate our AI-Endo with the Olympus endoscopic system and validate the AI-enabled cognitive assistance system with animal studies in live ESD training sessions. Dedicated data analysis from surgical phase recognition results is summarized in an automatically generated report for skill assessment.

Assessment of Rat Sciatic Nerve Using Diffusion-Tensor Imaging With Readout-Segmented Echo Planar Imaging.

Objectives: This study aimed to compare readout-segmented-3, readout-segmented-5, and readout-segmented-7 echo-planar imaging (RS3-EPI, RS5-EPI, and RS7-EPI) of DTI in the assessment of rat sciatic nerve at 3T MR. Methods: Eight male adult healthy Sprague-Dawley rats were scanned at 3T MR with RS-3 EPI, RS5-EPI, and RS-7 EPI DTI. The image quality of RS-3 EPI, RS-5 EPI, and RS-7 EPI in terms of the nerve morphology, distortions of the nearby femur, muscles, and homogeneity of neuromuscular were evaluated by two experienced radiologists. The correlations between the histopathological and DTI parameters, including fractional anisotropy (FA) and radial diffusivity (RD), were calculated, respectively, and compared in RS-3, RS-5, and RS-7 EPI. The image quality scores for RS-3 EPI, RS-5 EPI, and RS-7 EPI were compared using the Wilcoxon rank-sum test. The correlation between DTI and histopathological parameters was calculated using the Pearson correlation coefficient. Results: RS-5 EPI yielded the best SNR-values corrected for the acquisition time compared to RS3-EPI and RS7-EPI. The image quality scores of RS-5 EPI were superior to those of RS-3 and RS-7 EPI (P = 0.01-0.014) and lower artifacts of the ventral/dorsal margin and femur (P = 0.008-0.016) were shown. DTT analysis yielded a significantly higher number of tracts for RS5-EPI compared to RS3-EPI (P = 0.007) but no significant difference with RS7-EPI (P = 0.071). For the three sequences, FA and RD were well-correlated with the myelin-related histopathological parameters (|r| 0.709-0.965, P = 0.001-0.049). The overall correlation coefficients of FA and RD obtained from RS-5 EPI were numerically higher than that with both RS3-EPI and RS7-EPI. Conclusion: For the rat sciatic nerve DTI imaging, RS-5 EPI offered the best image quality and SNR-values corrected for the acquisition time. The FA and RD derived from the RS-5 EPI were the most sensitive quantitative biomarkers to detect rat sciatic nerve histopathological change.

ACEI and ARB Lower the Incidence of End-Stage Renal Disease among Patients with Diabetic Nephropathy: A Meta-analysis.

Objective: This study explores the effects of Angiotensin-Converting Enzyme Inhibitors (ACEI) or Angiotensin Receptor Blockers (ARB) on the incidence of end-stage renal disease (ESRD) in diabetic nephropathy (DN) patients. Methods: Literatures were searched in PubMed, Embase, Medline, CENTRAL, and CNKI databases. These literatures included a randomized controlled trial to evaluate the efficacy of ACEI and ARB among patients with DN. The endpoint event included the occurrence of ERSD. Risk ratio (RR) and 95% confidence interval (CI) were used to represent the combined effect size. A fixed-effect model was used to analyze if heterogeneity did not exist between literatures. If heterogeneity exists between literatures, a random-effect model was used to analyze. The source of heterogeneity was explored by subgroup analysis and sensitivity analysis. Results: A total of 11 literatures were included in the study. The RR of ESRD was 0.79 (95% CI (0.79, 0.90), Z = 3.58, P = 0.0003) in the patients treated with RAS blockers compared with placebo, and there was no heterogeneity between studies (Chi2 = 5.09, P = 0.88, I 2 = 0%). The funnel plot showed that the scatter point was biased to the left with publication bias. The RR of ESRD was 0.63 (95% CI (0.41, 0.95), Z = 2.18, P = 0.03) in the patients treated with ACEI compared with placebo. There was no heterogeneity between studies (Chi2 = 2.23, P = 0.95, I 2 = 0%). Compared with placebo, RR of ESRD among patients with ARB intervention was 0.81 (95% CI (0.71, 0.93), Z = 3.00, P = 0.003). There was no heterogeneity between studies (Chi2 = 1.49, P = 0.48, I 2 = 0%). Conclusion: ACEI and ARB can reduce the risk of ESRD among diabetic nephropathy patients.

Performance of Single-Shot Echo-Planar Imaging in Diffusion Tensor Imaging in Rat Sciatic Nerve Compared With Readout-Segmented Echo-Planar Imaging.

Objectives: To compare the performances of single-shot echo-planar imaging (SS-EPI) and readout-segmented echo-planar imaging (RS-EPI) for diffusion tensor imaging (DTI) of the rat sciatic nerve. Methods: Eight healthy adult male Sprague-Dawley rats were anesthetized and scanned with a 3T MRI scanner using SS-EPI and RS-EPI DTI sequences. The image quality in terms of the morphology of the nerve, distortions of the nearby femur, muscles, and homogeneity of neuromuscular were evaluated and scored. The correlations between the DTI parameters including fractional anisotropy (FA), axial diffusivity (AD), radial diffusivity (RD), apparent diffusion coefficient (ADC), and histopathological parameters were calculated by using the Pearson correlation coefficient and compared by the modified Fisher Z-transform, respectively. Results: The quality scores were higher for the images from the SS-EPI sequence compared with the RS-EPI sequence for characteristics such as sharpness of the sciatic nerve margin (P = 0.008), artifacts of the sciatic nerve (P = 0.008), and homogeneity of the neuromuscular region (P = 0.007), as well as the contrast-to-noise ratio (CNR) of DW images (P < 0.001). The correlation coefficients were higher for the FA and RD values from the SS-EPI sequence compared with those from the RS-EPI sequence. Furthermore, the correlation coefficients between FA and myelin thickness (P = 0.027), FA and diameter of the myelinated fiber (P = 0.036), as well as RD and myelin thickness (P = 0.05) were statistically higher for the SS-EPI sequence compared with those for the RS-EPI sequence. Conclusion: Diffusion tensor imaging analysis of the rat sciatic nerve showed that the image quality from the SS-EPI sequence was significantly higher compared with that from the RS-EPI sequence. Furthermore, the FA and RD derived from the SS-EPI sequence are promising and sensitive biomarkers to detect the histopathological changes in the rat sciatic nerve.

Chemoselective and Diastereoselective Intramolecular (3+2) Cycloadditions of Epoxy and Aziridinyl Enolsilanes.

Epoxy and aziridinyl enolsilanes react as oxyallylic cation equivalents in highly chemo- and diastereoselective intramolecular (3+2) cycloadditions with a range of dienes and olefins. With acyclic dienes, the (3+2) cycloaddition outcompetes the (4+3) pathway traditionally observed in this kind of system almost exclusively. With both conjugated dienes and isolated olefins, excellent diastereoselectivities are observed, and cycloadducts can be obtained in optically-enriched forms. Computational studies indicate that the stepwise (3+2) cycloaddition involves an activated epoxy/aziridinyl intermediate and the conformational flexibility of the intermediate determines the preference for (3+2) cycloadduct formation. Further transformations of the (3+2) cycloadducts produce densely functionalized trans-hydrindane scaffolds.

Magnetic resonance imaging assessment of the therapeutic effect of combined electroacupuncture and stem cells in acute peripheral nerve injury.

Objectives: This study aimed to evaluate the therapeutic effect of a combination of Bone Mesenchymal stem cells (BMSCs) transplantation and Electroacupuncture (EA) for acute sciatic nerve injury in rats using magnetic resonance. Methods: Ninety-two male adult healthy Sprague-Dawley rats were randomly divided into the EA+BMSCs group, EA group, MSCs group, and PBS group (control). Electroacupuncture was performed on a rat receiving EA treatment at Huantiao (GB30) and Zusanli (ST36). T2 values and diffusion tensor imaging (DTI) derived from multiparametric magnetic resonance imaging (MRI), histological assessments, and immunohistochemistry was used to monitor nerve regeneration. Walking track analysis was used to assess nerve functional recovery. Repeated-measures one-way analysis of variance was used to evaluate the significance of T2, DTI, and SFI values among the four groups. One-way analysis of variance was used for comparing the histological characteristics. Bonferroni test was used for multiple pairwise comparisons at each time point. Results: In terms of FA, the EA+BMSCs and EA groups had faster recovery than PBS (control) in all time points after surgery, and the EA+BMSCs group recovered better than the BMSCs group at 3 weeks (P ≤ 0.008). FA values were higher in the EA group than in the BMSCs group at 4 weeks (P ≤ 0.008). In terms of RD, the EA+BMSCs group recovered better than the BMSCs group at 2 and 4 weeks (P ≤ 0.008). Immunofluorescence staining for axon guidance molecule netrin-1 revealed that it was significantly higher in the EA+BMSCs subgroup and EA subgroup than it was in the control (PBS) subgroup at 1-3 weeks (P < 0.001). Immunofluorescence staining for S100 showed the continuity of nerve fibers recovered more quickly in the EA+BMSCs subgroup than in the BMSCs subgroup. Conclusion: Our research revealed that a combination of MSCs and EA can provide both topological and biomolecular guidance to promote axonal extension, myelin regeneration, and functional recovery after PNI. EA not only promotes nerve repair on its own, but also enhanced the beneficial effects of stem cell treatment and the secretion of netrin 1, a guidance regeneration factor, and promotes the orderly growth of nerve fibers. These PNI repairs could be monitored non-invasively and in situ by MRI. The FA and RD values derived from MRI could be sensitive biomarkers to reflect the PNI repair process.

Fat- and iron-corrected ADC to assess liver fibrosis in patients with chronic hepatitis B.

PURPOSE: We aimed to evaluate the diagnostic performance of apparent diffusion coefficient (ADC) in assessing liver fibrosis after correcting for the effects of hepatic steatosis or iron deposition. METHODS: Seventy-three patients with chronic hepatitis B (CHB) were included in this retrospective study. The aspartate aminotransferase-to-platelet ratio index (APRI) was calculated for classification of the fibrosis grade. Significant fibrosis and cirrhosis were diagnosed with the APRI. The proton density fat fraction (PDFF), R2*, and ADC values were measured. The impact of the PDFF and R2* on the ADC was analyzed. The PDFF- and R2*-corrected ADC values (ADCPDFF and ADCR2*) were calculated according to linear regression equations. The diagnostic performance of uncorrected ADC (ADCu), ADCPDFF and ADCR2* in predicting significant fibrosis and cirrhosis was assessed, and the area under the curve (AUC) values were compared. RESULTS: Among the 73 patients in this study, the mean ADC was 0.866 ± 0.084×10-3 mm2/s, the mean R2* was 60.24 (42.77, 85.37) 1/s, and the mean PDFF was 2.90% (1.60%- 4.80%). The ADC was negatively correlated with the PDFF (r= -0.298, P = .010) and R2* (r = -0.457, P < .001). Linear regression analysis showed that the PDFF and R2* were independent factors of the ADC (ß= -0.315, P = .007, R2= 0.099 and ß= -0.493, P < .001, R2= 0.243, respectively). Compared with the uncorrected ADC (r= -0.307, P = .022), the correlation between the ADCPDFF and fibrosis grade increased (r= -0.513, P < .001), and the correlation between the ADCR2* and fibrosis grade decreased (r=-0.168, P = .215). The AUC of the ADCPDFF was significantly larger than that of the ADCu in the diagnosis of significant fibrosis and cirrhosis, which increased from 0.68 to 0.81 (P = .003) for predicting significant fibrosis and from 0.75 to 0.84 (P = .009) for predicting cirrhosis. The AUCs for the ADCR2* in the diagnosis of significant fibrosis and cirrhosis were both lower than that for the uncorrected ADC (P = .206 and P = .109, respectively). CONCLUSION: After correcting for the effects of steatosis, the diagnostic performance of the ADC for signifi-cant fibrosis and cirrhosis increased. The ADC corrected for the effects of steatosis may be more reliable for identifying liver fibrosis.

Altered Topological Patterns of Gray Matter Networks in Tinnitus: A Graph-Theoretical-Based Study.

OBJECTIVE: Tinnitus is a prevalent hearing disorder, which could have a devastating impact on a patient's life. Functional studies have revealed connectivity pattern changes in the tinnitus brains that suggested a change of network dynamics as well as topological organization. However, no studies have yet provided evidence for the topological network changes in the gray matter. In this research, we aim to use the graph-theoretical approach to investigate the changes of topology in the tinnitus brain using structural MRI data, which could provide insights into the underlying anatomical basis for the neural mechanism in generating phantom sounds. METHODS: We collected 3D MRI images on 46 bilateral tinnitus patients and 46 age and gender-matched healthy controls. Brain networks were constructed with correlation matrices of the cortical thickness and subcortical volumes of 80 cortical/subcortical regions of interests. Global network properties were analyzed using local and global efficiency, clustering coefficient, and small-world coefficient, and regional network properties were evaluated using the betweenness coefficient for hub connectivity, and interregional correlations for edge properties. Between-group differences in cortical thickness and subcortical volumes were assessed using independent sample t-tests, and local efficiency, global efficiency, clustering coefficient, sigma, and interregional correlation were compared using non-parametric permutation tests. RESULTS: Tinnitus was found to have increased global efficiency, local efficiency, and cluster coefficient, indicating generally heightened connectivity of the network. The small-world coefficient remained normal for tinnitus, indicating intact small-worldness. Betweenness centrality analysis showed that hubs in the amygdala and parahippocampus were only found for tinnitus but not controls. In contrast, hubs in the auditory cortex, insula, and thalamus were only found for controls but not tinnitus. Interregional correlation analysis further found in tinnitus enhanced connectivity between the auditory cortex and prefrontal lobe, and decreased connectivity of the insula with anterior cingulate gyrus and parahippocampus. CONCLUSION: These findings provided the first morphological evidence of altered topological organization of the brain networks in tinnitus. These alterations suggest that heightened efficiency of the brain network and altered auditory-limbic connection for tinnitus, which could be developed in compensation for the auditory deafferentation, leading to overcompensation and, ultimately, an emotional and cognitive burden.

Monitoring of macrophage recruitment enhanced by Toll-like receptor 4 activation with MR imaging in nerve injury.

INTRODUCTION: Macrophage recruitment is critical for nerve regeneration after an injury. The aim of this study was to investigate whether ultrasmall superparamagnetic iron oxide (USPIO) nanoparticle-based MRI could be used to monitor the enhanced macrophage recruitment by Toll-like receptor 4 (TLR4) activation in nerve injury. METHODS: Rats received intraperitoneal injections of either lipopolysaccharide (LPS) or phosphate buffered saline (PBS) or no injection (controls) after a sciatic nerve crush injury. After intravenous injection of the USPIOs (LPS and PBS groups) or PBS (control group), MRI was performed and correlated with histological findings. RESULTS: LPS group showed more remarkable hypointense signals on T2*-weighted imaging and lower T2 values in the crushed nerves than PBS group. The hypointense signal areas were associated with an enhanced recruitment of iron-loaded macrophages to the injured nerves. DISCUSSION: USPIO-enhanced MRI can be used to monitor the enhanced macrophage recruitment by means of TLR4 signal pathway activation in nerve injury. Muscle Nerve, 2018.

Assessment of the synergic effect of immunomodulation on nerve repair using multiparametric magnetic resonance imaging.

INTRODUCTION: The immune system plays a pivotal role in nerve injury. The aim of this study was to determine the role of multiparametric magnetic resonance imaging (MRI) in evaluation of the synergic effect of immunomodulation on nerve regeneration in neurotmesis. METHODS: Rats with sciatic nerve neurotmesis and surgical repair underwent serial multiparametric MR examinations over an 8-week period after subepineurial microinjection of lipopolysaccharide (LPS) and subsequent subcutaneous injection of FK506 or subepineurial microinjection of LPS or phosphate-buffered saline (PBS) alone. RESULTS: Nerves treated with immunomodulation showed more prominent regeneration than those treated with LPS or PBS alone and more rapid restoration toward normal T2, fractional anisotropy (FA), and radial diffusivity (RD) values than nerves injected with LPS or PBS. DISCUSSION: Nerves treated with immunomodulation exert synergic beneficial effects on nerve regeneration that can be predicted by T2 measurements and FA and RD values. Muscle Nerve 57: E38-E45, 2018.

DTI metrics can be used as biomarkers to determine the therapeutic effect of stem cells in acute peripheral nerve injury.

PURPOSE: To determine the role of diffusion tensor imaging (DTI) metrics as biomarkers for the therapeutic effects of mesenchymal stem cells (MSCs) in acute peripheral nerve injury. MATERIALS AND METHODS: Forty-four adult rats received subepineurial microinjection of MSCs (n = 22) or phosphate buffered saline (PBS, n = 22) 1 week after the sciatic nerve trunk crush injury. Sequential fat-suppressed T2-weighted imaging, T2 measurement, DTI and sciatic nerve functional assessment were performed at a 3.0 Tesla MR unit over an 8-week follow-up, with histological assessments performed at regular intervals. The sciatic nerve function index, T2 value, and DTI metrics, including fractional anisotropy (FA), axial diffusivity, radial diffusivity (RD), and mean diffusivity values of the distal stumps of crushed nerves were measured and compared between the two groups. RESULTS: Nerves treated with MSCs showed better functional recovery and exhibited more pronounced nerve regeneration compared with nerves treated with PBS. T2 values in nerves treated with MSCs or PBS showed a similar change pattern (P = 0.174), while FA and RD values in nerves treated with MSCs showed more rapid return (one week earlier) to baseline level than nerves treated with PBS (P = 0.045; 0.035). Nerves treated with MSCs had higher FA and lower RD values than nerves treated with PBS during the period from 2 to 3 weeks after surgery (P ≤ 0.0001, 0.004; P = 0.004, 0.006). CONCLUSION: FA and RD values derived from DTI might be used as sensitive biomarkers for detecting the therapeutic effect of stem cells in acute peripheral nerve crush injuries. LEVEL OF EVIDENCE: 2 J. Magn. Reson. Imaging 2017;45:855-862.

Assessment of diabetic peripheral neuropathy in streptozotocin-induced diabetic rats with magnetic resonance imaging.

OBJECTIVE: To determine the role of magnetic resonance (MR) imaging and quantitative T2 value measurements in the assessment of diabetic peripheral neuropathy (DPN). METHODS: Sequential MR imaging, T2 measurement, and quantitative sensory testing of sciatic nerves were performed in streptozotocin-induced diabetic rats (n = 6) and normal control rats (n = 6) over a 7-week follow-up period. Histological assessment was obtained from 48 diabetic rats and 48 control rats once weekly for 7 weeks (n = 6 for each group at each time point). Nerve signal abnormalities were observed, and the T2 values, mechanical withdrawal threshold (MWT), and histological changes were measured and compared between diabetic and control animals. RESULTS: Sciatic nerves in the diabetic rats showed a gradual increase in T2 values beginning at 2 weeks after the induction (P = 0.014), while a decrease in MWT started at 3 weeks after the induction (P = 0.001). Nerve T2 values had a similar time course to sensory functional deficit in diabetic rats. Histologically, sciatic nerves of diabetic rats demonstrated obvious endoneural oedema from 2 to 3 weeks after the induction, followed by progressive axonal degeneration, Schwann cell proliferation, and coexistent disarranged nerve regeneration. CONCLUSION: Nerve T2 measurement is potentially useful in detecting and monitoring diabetic neuropathy. KEY POINTS: • Sciatic nerves in diabetic rats showed a gradual increase in T2 values • Nerve T2 values were negatively correlated with sensory function impairment • Longitudinal T2 values can be used to monitor the disease progress • Nerve degeneration contributed mainly to progressive prolongation of nerve T2 values.

Diffusion tensor imaging of symptomatic nerve roots in patients with cervical disc herniation.

RATIONALE AND OBJECTIVES: Cervical disc degeneration can result in nerve root compression and severe symptoms that significantly impair the patient's quality of life. The purpose of this study is to investigate multiple diffusion metrics changes in the diffusion tensor imaging (DTI) of cervical nerve roots and their relationship with the clinical severity of patients with cervical disc herniation. MATERIALS AND METHODS: High directional DTI of the cervical nerve roots was performed in 18 symptomatic patients and 10 healthy volunteers with a 3.0-T magnetic resonance system after a routine cervical disc scanning. The fractional anisotropy (FA), mean diffusivity (MD), axial diffusivity (AD), and radial diffusivity (RD) were calculated from the DTI data and compared between the affected and unaffected sides in the same patient and between healthy volunteers and symptomatic patients. The correlation between the side-to-side diffusion metric differences and the clinical International Standards for Neurological Classification of Spinal Cord Injury scores was analyzed. RESULTS: C5-C8 nerve roots were clearly delineated with DTI. The FA, MD, AD, and RD of compressed nerve roots were 0.31 ± 0.091, 2.06 ± 0.536, 2.69 ± 0.657, and 1.75 ± 0.510 mm(2)/s, respectively. Compared to the unaffected side or healthy volunteers, the nerve roots of the affected side showed decreased FA (P < .022) and increased MD (P < .035), AD (P < .047), and RD (P < .012). The clinical International Standards for Neurological Classification of Spinal Cord Injury scores of the patients were negatively correlated with MD (r = -0.57, P = .002), AD (r = -0.451, P = .021), and RD (r = -0.564, P = .003) but not with FA (r = 0.004, P = .984). CONCLUSIONS: DTI can potentially be used to assess microstructural abnormalities in the cervical nerve roots in patients with disc herniation.