A mutant MATR3 mouse model to explain multisystem proteinopathy

Mutations in the Matrin 3 (MATR3) gene have been identified as a cause of amyotrophic lateral sclerosis (ALS) or vocal cord and pharyngeal weakness with distal myopathy (VCPDM). This study investigated the mechanism by which mutant MATR3 causes multisystem proteinopathy (MSP) including ALS and VCPDM. We first analyzed the muscle pathology of C57BL/6 mice injected with adeno-associated viruses expressing human WT or mutant (S85C) MATR3. We next generated transgenic mice that overexpress mutant (S85C) MATR3, driven by the CMV early enhancer/chicken β-actin promoter, and evaluated their clinicopathological features. Intramuscular injection of viruses expressing WT and mutant MATR3 induced similar myogenic changes, including smaller myofibers with internal nuclei, and upregulated p62 and LC3-II. Mutant MATR3 transgenic mice showed decreased body weight and lower motor activity. Muscle histology demonstrated myopathic changes including fiber-size variation, internal nuclei and rimmed vacuoles. Spinal cord histology showed a reduced number of motor neurons, and activation of microglia and astrocytes. Comprehensive proteomic analyses of muscle demonstrated upregulation of proteins related to chaperones, stress response, protein degradation, and nuclear function. Overexpression of WT and mutant MATR3 similarly caused myotoxicity, recapitulating the clinicopathological features of MSP. These models will be helpful for analyzing MSP pathogenesis and for understanding the function of MATR3. © 2019 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.     

Imaging scoring systems for preoperative molecular diagnoses of lower-grade gliomas

Neurosurgical Review - Recent advance in molecular characterization of gliomas showed that patient prognosis and/or tumor chemosensitivity correlate with certain molecular signatures; however, this...     

Synthetic MRI with T2-based Water Suppression to Reduce Hyperintense Artifacts due to CSF–Partial Volume Effects in the Brain

Purpose:Our purpose was to assess our proposed new synthetic MRI (synMRI) technique, combined with T₂-based water suppression (T₂wsup), to reduce cerebral spinal fluid (CSF)–partial volume effects (PVEs). These PVEs are problematic in the T₂-weighted fluid-attenuation inversion recovery (FLAIR) images obtained by conventional synMRI techniques.Methods:Our T₂wsup was achieved by subtracting additionally acquired long TE spin echo (SE) images of water signals dominant from the originally acquired images after T₂ decay correction and a masking on the long TE image using the water volume (V_w) map to preserve tissue SNR, followed by quantitative mapping and then calculation of the synthetic images. A simulation study based on a two-compartment model including tissue and water in a voxel and a volunteer MR study were performed to assess our proposed method. Parameters of long TE and a threshold value in the masking were assessed and optimized experimentally. Quantitative parameter maps of standard and with T₂wsup were generated, then wsup-synthetic FLAIR and SE images were calculated using those suitable combinations and compared.Results:Our simulation clarified that the CSF–PVE artifacts in the standard synthetic FLAIR increase T₂ as the water volume increases in a voxel, and the volunteer MR brain study demonstrated that the hyperintense artifacts on synthetic images were reduced to < 10% of V_w in those with the standard synMRI while keeping the tissue SNR by selecting optimal masking parameters on additional long TE images of TE = 300 ms. In addition, the wsup-synthetic SE provided better gray-white matter contrasts compared with the wsup-synthetic FLAIR while keeping CSF suppression.Conclusion:Our proposed T₂wsup-synMRI technique makes it easy to reduce the CSF–PVE artifacts problematic in the synthetic FLAIR images using the current synMRI technique by adding long TE images and simple processing. Although further optimizations in data acquisition and processing techniques are required before actual clinical use, we expect our technique to become clinically useful.     

Potential role of transient receptor potential (TRP) channels in bladder cancer cells

Transient receptor potential (TRP) channels play important roles in thermal, chemical, and mechanical sensation in various tissues. In this study, we investigated the differences in urothelial TRP channels between normal urothelial cells and bladder cancer cells. TRPV2 and TRPM7 expression levels and TRPV2 activator-induced intracellular Ca²⁺ increases were significantly higher, whereas TRPV4 expression and TRPV4 activator-induced intracellular Ca²⁺ increases were significantly lower in mouse bladder cancer (MBT-2) cells compared to normal mouse urothelial cells. The proliferation rate of MBT-2 cells overexpressing dominant-negative TRPV2 was significantly increased. In contrast, treatment with TRPV2 activators significantly decreased the proliferation rate. TRPM7-overexpressing MBT-2 cells proliferated more slowly, as compared to mock-transfected cells. Moreover, expression of dominant-negative TRPV2 significantly decreased plasma membrane Ca²⁺ permeability of MBT-2 cells as compared to that in mock-transfected cells. Increases in the expression of TRPV2 mRNA, immunoreactivity, and TRPV2 activator-induced intracellular Ca²⁺ were also observed in T24 human bladder cancer cells. These results suggested that TRPV2 and TRPM7 were functionally expressed in bladder cancer cells and served as negative regulators of bladder cancer cell proliferation, most likely to prevent excess mechanical stresses.     

Pre-hospital Diagnosis of Large Vessel Occlusion in Patients Being Transported by Helicopter

BackgroundDuring the helicopter transportation of patients suspected of large vessel occlusion (LVO), an accurate and rapid decision-making process is required.AimsWe attempted to create an algorithm for the pre-hospital diagnosis of the presence of LVO in patients suspected of stroke using data from patients transported urgently by helicopter.MethodsOne hundred and sixty-five patients transported by helicopter were divided into two subgroups: a training dataset and a validation dataset. We extracted clinical information obtained on site, the unadjusted score of the National Institutes of Health Stroke Scale, and previously reported pre-hospital scales as an LVO screen. On the basis of the analyses of these factors, an algorithm was devised to predict the presence of LVO and its predictive accuracy was evaluated using the validation dataset.ResultsIschemic stroke with LVO was diagnosed in 36 out of 121 cases (29.8%) in the training dataset and in 10 out of 44 cases (22.7%) in the validation dataset. Combining five factors (conjugate deviation, upper limb paresis, atrial fibrillation, Japan Coma Scale ≥ 200, and systolic blood pressure ≥ 180), an algorithm was created to classify cases into six groups with different likelihoods of LVO presence. The algorithm predicted correctly 6 out of 10 cases in the validation dataset. Furthermore, it definitively ruled out 17 out of 34 cases in the validation dataset.ConclusionsUsing the newly created algorithm, emergency staff could easily and accurately distinguish patients suitable for urgent endovascular thrombectomy from patients with non-LVO or stroke mimics.     

Bladder wall injection of mesenchymal stem cells ameliorates bladder inflammation,overactivity, and nociception in a chemically induced interstitial cystitis-like rat model

Introduction and hypothesis

We investigated the effects of bladder wall injection of mesenchymal stem cells (MSCs) on bladder tissues, function, and nociceptive behavior in a chemically induced interstitial cystitis-like rat model.

Methods

Chemical cystitis of female rats was induced by intravesical instillation of 0.1 N hydrochloride (HCl) once a week for 2 weeks. Bladders were harvested 1, 2, 3, and 4 weeks after the second application for histological examination. Adipose-derived MSCs (HCl?+?MSCs) or phosphate-buffered saline (HCl?+?PBS) was injected into the bladder wall at the time of the second application of HCl. Histological examination, nociceptive behavior, and cystometrograms were evaluated 2 weeks after the injection compared with controls, which received instillation and injection of PBS into the bladder (sham + PBS).

Results

The number of mast cells and expression of tumor necrosis factor-α (TNF-α) and transforming growth factor-β (TGF-β) were significantly increased at 1 and 2 weeks, and expression of collagen fibers was significantly increased from 2–4 weeks after the second application of HCl. Significantly increased nociceptive behavior, number of mast cells, expression of TNF-α, TGF-β, and collagen fibers were observed in HCl?+?PBS compared with sham?+?PBS, whereas these changes were significantly decreased in HCl?+?MSCs compared with HCl?+?PBS. In addition, bladder capacity and voiding threshold pressures were significantly decreased in HCl?+?PBS but not in HCl?+?MSCs compared with sham?+?PBS.

Conclusions

The results suggest that bladder injection of MSCs ameliorates inflammation and fibrosis in bladder tissues, bladder overactivity, and nociception in a rat model of chemically induced cystitis.