Search

BACKGROUND AND PURPOSE: In spastic paraplegia type 5, spinal cord atrophy and white matter signal abnormalities in the brain are the main MR imaging alterations. However, the specific mechanism remains unclear. We explored the microstructural changes occurring in spastic paraplegia type 5 and assessed the relation between MR imaging and clinical data. MATERIALS AND METHODS: Seventeen patients with spastic paraplegia type 5 and 17 healthy controls were scanned with DTI and T1 mapping on a 3T MR imaging scanner. Fractional anisotropy, mean diffusivity, radial diffusivity, axial diffusivity, and T1 values were obtained using Tract-Based Spatial Statistics and the Spinal Cord Toolbox. Neurofilament light and myelin basic protein in the CSF were measured. The differences in MR imaging and biochemical data between patients with spastic paraplegia type 5 and healthy controls were compared using the Student t test. RESULTS: A widespread reduction of fractional anisotropy values and an elevation of mean diffusivity, T1, and radial diffusivity values were found in most cervical, T4, and T5 spinal cords; corona radiata; optic radiations; and internal capsules in spastic paraplegia type 5. A variation in axial diffusivity values was shown only in C2, C6, and the corona radiata but not in the gray matter. The levels of neurofilament light and myelin basic protein were higher in those with spastic paraplegia type 5 than in healthy controls (myelin basic protein, 3507 [SD, 2291] versus 127 [SD, 219] pg/mL; neurofilament light, 617 [SD, 207] versus 265 [SD, 187] pg/mL; P

BACKGROUND CONTEXT Lumbar intervertebral disc herniation (LDH) is a common disease that causes low back pain, radiating leg pain, and sensory impairment. Preclinical studies rely heavily upon standardized animal models of human diseases to predict clinical treatment efficacy and to identify and investigate potential adverse events in human subjects. The current method for making the LDH model involves harvesting the nucleus pulposus (NP) from autologous coccygeal discs and applying to the lumbar nerve roots just proximal to the corresponding dorsal root ganglion. However, this surgical method generates a model that exhibits very different characteristics of disc herniation than that observed in human. PURPOSE To produce a rat LDH model that better resembles disc herniation in humans and a standardized and uniform LDH model using Interleukin-1 beta (IL-1β). STUDY DESIGN Experimental rat LDH model. METHODS We exposed the L5–6 disc dorsolaterally on the right side through hemi-laminectomy without nerve compression. Herniation was initiated by puncturing the exposed disc with a 30-gauge needle at a depth of 4 mm. Interleukin-1 beta (IL-1β) was injected simultaneously to heighten the pathological processes of disc degeneration, including inflammatory responses, matrix destruction, and herniation of the NP. We performed histological staining to assess morphological changes, immunohistochemistry to analyze inflammation- and pain-related expression within and around the puncture site of the L5–6 disc, and real-time polymerase chain reaction to examine expression of markers for degenerative processes. In addition, we performed locomotor tests on the rats. RESULTS We found that the IL-1β groups showed that the border between the annulus fibrosis and nucleus pulposus was severely interrupted compared to that of the control (puncture only) group. And, the injection of IL-1β leads to accelerated disc degeneration and inflammation in a more consistent manner in LDH model. Functional deficit was consistently induced by puncturing and injection of IL-1β in the exposed disc. CONCLUSIONS The method proposed here can be used as an index to control the severity of disc degeneration and inflammation through the injected IL-1β concentration concurrent with surgically induced herniation. CLINICAL SIGNIFICANCE Our proposed model may facilitate research in drug development to evaluate the efficacy of potential therapeutic agents for disc herniation and neuropathic pain and may also be used for nonclinical studies to more accurately assess the effectiveness of various treatment strategies according to the severity of disc degeneration.

The purpose of this study was to assess the clinicopathologic implications of tumor spread through air spaces (STAS) in patients with stage IA part-solid lung adenocarcinoma after sublobar resection.Medical records of patients with stage IA part-solid adenocarcinoma who underwent curative pulmonary resection between February 2009 and December 2016 were retrospectively reviewed. The clinicopathological features of STAS and its influence on postoperative recurrence and survival were investigated.Among the 115 patients with stage IA part-solid adenocarcinoma who underwent wedge resection, 20 (17.4 %) had STAS. The multivariable analysis showed presence of STAS [HR (hazard ratio), 9.447; p = 0.002) and a larger invasive component size (HR, 1.097; p = 0.034) were independent risk factors for recurrence. The 5-year freedom from recurrence rates were 62.4 % and 97.9 % in cases with and without STAS, respectively (p 0.001), and the 5-year disease-free survival rates were 58.5 % and 97.9 % in cases with and without STAS, respectively (p 0.001). The presence of STAS was associated with old age (p = 0.030), male gender (p = 0.023), acinar predominant histologic pattern (p = 0.004), presence of micropapillary pattern (p 0.001), lymphovascular invasion (p 0.001) and larger invasive component (p 0.001).STAS could be an important prognostic factor in patients with stage IA part-solid lung adenocarcinoma after sublobar resection. Effective preoperative evaluation and postoperative surveillance may help improve the outcome of patients with small part-solid nodules, particularly when accompanied by STAS.

Background Wilson disease is a rare, disabling, neurological genetic disease. Biomarkers of brain damage are less well developed. Objective The aim of this study was to evaluate the utility of plasma glial fibrillary acidic protein as a biomarker for neurological involvement in patients with Wilson disease. Methods This prospective cross-observational study compared plasma glial fibrillary acidic protein concentration among different subtypes of patients with Wilson disease and healthy control subjects. Plasma glial fibrillary acidic protein levels were measured in 94 patients and 25 healthy control subjects. Patients were divided into two subtypes: patients with neurological manifestations (n = 74) or hepatic manifestations (n = 20). Results Median levels of plasma glial fibrillary acidic protein were significantly elevated in patients with neurological manifestations (143.87 pg/mL) compared with those with hepatic manifestations (107.50 pg/mL) and healthy control subjects (86.85 pg/mL). Receiver operating characteristic curve revealed that a plasma glial fibrillary acidic protein cutoff value of 128.8 pg/mL provides sufficient sensitivity (80.0%) and specificity (63.5%) to differentiate patients with neurological manifestations from those with hepatic manifestations. Conclusions Plasma glial fibrillary acidic protein may serve as a biomarker for distinguishing different subtypes of Wilson disease. © 2021 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Objective Recessive mutations in the CAPN1 gene have recently been identified in spastic paraplegia 76 (SPG76), a complex hereditary spastic paraplegia (HSP) that is combined with cerebellar ataxia, resulting in an ataxia‐spasticity disease spectrum. This study aims to assess the influence of CAPN1 variants on the occurrence of SPG76 and identify factors potentially contributing to phenotypic heterogeneity. Methods We screened a cohort of 240 unrelated HSP families for variants in CAPN1 using high‐throughput sequencing analysis. We described in detail the clinical and genetic features of the SPG76 patients in our cohort and summarized all reported cases. Results Six unreported CAPN1‐associated families containing eight patients with or without cerebellar ataxia were found in our cohort of HSP cases. These patients carried three previously reported homozygous truncating mutations (p.V64Gfs*103, c.759+1G>A, and p.R285*), and three additional novel compound heterozygous missense mutations (p.R481Q, p.P498L, and p.R618W). Lower limbs spasticity, hyperreflexia, and Babinski signs developed in about 94% of patients, with ataxia developing in 63% of cases. In total, 33 pathogenic mutations were distributed along the three reported functional domains of calpain‐1 protein, encoded by CAPN1, with no hotspot region. A comparison of gender distribution between the two groups indicated that female SPG76 patients were significantly more likely to present with complicated HSP than male patients (P = 0.015). Interpretation Our study supports the clinically heterogeneous inter‐ and intra‐family variability of SPG76 patients, and demonstrates that gender and calpain‐1 linker structure may contribute to clinical heterogeneity in SPG76 cases.

Objective Spinocerebellar ataxia type 3 (SCA3) is one of the most common hereditary neurodegenerative diseases, with balance instability as main symptom. Balance quantification is crucial for evaluating the efficacy of therapeutic interventions. However, balance evaluation in SCA3 is often subject to bias. Here, we aimed to quantitatively evaluate postural instability and investigate the relationship between postural instability and clinical characteristics in SCA3 patients. Methods Sixty‐two SCA3 patients and 62 normal controls were recruited, and their postural balance was measured using a posturographic platform. Principal component analysis was performed as data reduction to identify postural instability factors. Multivariable linear regression was used to investigate potential risk factors for postural instability and to explore whether postural instability predicts the severity and progression of ataxia in SCA3 patients. Results We found SCA3 patients experience postural instability characterized by significant impairment in static and dynamic stability. The condition without visual feedback was the most sensitive measure in differentiating SCA3 from controls. Regression analyses revealed that ataxia severity predicted both static (P = 0.014) and dynamic stability (P = 0.001). Likewise, along with expanded CAG repeats (P

PURPOSE: The current study aims to determine the molecular mechanisms of diabetic retinopathy (DR) using the protein-protein interactome and metabolome map. We examined the protein network of novel biomarkers of DR for direct (physical) and indirect (functional) interactions using clinical target proteins in different models. METHODS: We used proteomic tools including 2-dimensional gel electrophoresis, mass spectrometry analysis, and database search for biomarker identification using in vivo murine and human model of diabetic retinopathy and in vitro model of oxidative stress. For the protein interactome and metabolome mapping, various bioinformatic tools that include STRING and OmicsNet were used. RESULTS: We uncovered new diabetic biomarkers including prohibitin (PHB), dynamin 1, microtubule-actin crosslinking factor 1, Toll-like receptor (TLR 7), complement activation, as well as hypothetical proteins that include a disintegrin and metalloproteinase (ADAM18), vimentin III, and calcium-binding C2 domain-containing phospholipid-binding switch (CAC2PBS) using a proteomic approach. Proteome networks of protein interactions with diabetic biomarkers were established using known DR-related proteome data. DR metabolites were interconnected to establish the metabolome map. Our results showed that mitochondrial protein interactions were changed during hyperglycemic conditions in the streptozotocin-treated murine model and diabetic human tissue. CONCLUSIONS: Our interactome mapping suggests that mitochondrial dysfunction could be tightly linked to various phases of DR pathogenesis including altered visual cycle, cytoskeletal remodeling, altered lipid concentration, inflammation, PHB depletion, tubulin phosphorylation, and altered energy metabolism. The protein-metabolite interactions in the current network demonstrate the etiology of retinal degeneration and suggest the potential therapeutic approach to treat DR. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1007/s40200-020-00570-9) contains supplementary material, which is available to authorized users.

PURPOSE: The current study aimed to determine the antidiabetic effects of leaf extract of Ficus asperifolia in streptozotocin-induced diabetic rats. METHODS: A total of ninety-five (95) adult rats were used for the experiment. The whole study protocol was divided into three sets of individual experiments. The animals were divided randomly into seven groups of five rats each. The rats were given a diet supplemented with 50 g high fat to 50 g vital feeds for two weeks. The study lasted 28 days with daily administration and weekly blood glucose and body weight check. At the end of the experiment protocol, the rats were fasted overnight and were anesthetized. Blood was collected via cardiac puncture from each animal for biochemical analysis. Metglim 3.38 mg/kg bodyweight was used as positive control. Diabetes was induced using streptozotocin (35 mg/kg in 0.1 M phosphate-buffered saline) intraperitoneally for 5 days. Phytochemicals were analyzed in both extract and fractions. RESULTS: Phytochemical screening revealed the presence of alkaloids, saponins, flavonoids, glycosides, tannins, carotenoids, terpenes, and steroids in both extract and fractions. Proteins, carbohydrates, and fats were detected by systematic molecular analysis. Fraction 1 of plant extracts prevented glucose-induced hyperglycaemia 30 min’ post glucose load in all rats. Streptozotocin treatment caused a significant increase (p˂0.05) in blood sugar, total cholesterol, triacylglycerol, low-density lipoproteins and a significant (p˂0.05) decrease in food intake, body weight and high-density lipoproteins in diabetic rats. CONCLUSION: Treatment with the extract significantly improved the derangements caused by streptozotocin. These results suggest that the leaf extracts of Ficus asperifolia could serve as a potential treatment for diabetes therapy. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1007/s40200-020-00524-1) contains supplementary material, which is available to authorized users.

BACKGROUND Infantile hemangioma (IH) can lead to severe complications. The 595-nm pulsed dye laser is poorly effective on thick and deep IH. Long-pulsed alexandrite laser has the proper wavelength of 755 nm and a relatively deep penetration. Thus, this may be a safe and effective treatment method for relatively deep or thick IH. AIMS AND OBJECTIVES This study aims to determine whether 595-nm pulsed dye laser and 755-nm long-pulsed alexandrite laser in sequential therapy are safer and more effective for relatively deep or thick hemangioma. MATERIALS AND METHODS This was a prospective study. A total of 194 infantile IH patients (thickness greater than 2 mm and less than 8 mm) were randomly divided into two groups: control group (treated using 595-nm pulsed dye laser) and experimental group (treated by sequential therapy with 755-nm long-pulsed alexandrite laser and 595-nm dye laser). RESULTS The control group had a total effective rate of 36.1%, while the experimental group had a total effective rate of 76.3%. Enumeration data were compared by X2 -test. The results were considered statistically significant at P

Hemorrhagic fever with renal syndrome (HFRS), caused by hantavirus, is occasionally seen in tropical areas. The virus is carried by specific rodent host species. Hemorrhagic fever with renal syndrome is characterized by renal failure and hemorrhagic manifestations, and its complications may be severe, including massive bleeding, multi-organ dysfunction, and possibly death. In this patient case, a 46-year-old woman diagnosed with HFRS initially presented with fever, impaired renal function, and thrombocytopenia. Four days after symptom onset, the patient complained of abrupt right lower abdominal pain and numbness. Magnetic resonance imaging revealed a spinal subarachnoid hemorrhage (SAH) beyond the T7 to S2 vertebrae. No cases of spinal SAH in HFRS have been reported until now. This case demonstrates that when a patient’s symptoms are atypical, bleeding-related complications must be considered.

Primary familial brain calcification (PFBC) is a progressive neurological disorder manifesting as bilateral brain calcifications in CT scan with symptoms as parkinsonism, dystonia, ataxia, psychiatric symptoms, etc. Recently, pathogenic variants in MYORG have been linked to autosomal recessive PFBC. This study aims to elucidate the mutational and clinical spectrum of MYORG mutations in a large cohort of Chinese PFBC patients with possible autosomal recessive or absent family history. Mutational analyses of MYORG were performed by Sanger sequencing in a cohort of 245 PFBC patients including 21 subjects from 10 families compatible with a possibly autosomal-recessive trait and 224 apparently sporadic cases. In-depth phenotyping and neuroimaging features were investigated in all patients with novel MYORG variants. Two nonsense variants (c.442C > T, p. Q148*; c.972C > A, p. Y324*) and two missense variants (c.1969G>C, p. G657R; c.2033C > G, p. P678R) of MYORG were identified in four sporadic PFBC patients, respectively. These four novel variants were absent in gnomAD, and their amino acid were highly conserved, suggesting these variants have a pathogenic impact. Patients with MYORG variants tend to display a homogeneous clinical spectrum, showing extensive brain calcification and parkinsonism, dysarthria, ataxia, or vertigo. Our findings supported the pathogenic role of MYORG variants in PFBC and identified two pathogenic variants (c.442C > T, c.972C > A), one likely pathogenic variant (c.2033C > G), and one variant of uncertain significance (c.1969G>C), further expanding the genetic and phenotypic spectrum of PFBC-MYORG.

To determine the association of age-related macular degeneration (AMD) with Alzheimer disease (AD) and Parkinson disease (PD).Retrospective cohort study.The study population consisted of 308,340 participants aged 50 years or older from the Korean National Health Insurance Service-Health Screening Cohort. After exclusion of participants with AMD during 2002, participants were detected for AMD during 2003-2005. Starting from January 1, 2006, all participants were followed up for AD and PD until December 31, 2013. Multivariate Cox proportional hazards regression was used to calculate the adjusted hazard ratios (aHRs) and 95% confidence intervals (CIs) for AD and PD risk.Compared to non-AMD participants, AMD patients had higher risk for AD (aHR 1.48, 95% CI 1.25-1.74) and PD (aHR 1.46, 95% CI 1.14-1.88). The risk-increasing association of AMD with AD (aHR 2.25, 95% CI 1.39-3.66) and PD (aHR 2.02, 95% CI 1.00-4.08) were preserved among participants who were never-smokers, did not consume alcohol, and exercised regularly. Finally, AMD was associated with higher risk of AD (aHR 1.96, 95% CI 1.46-2.65 for age70 years and aHR 1.53, 95% CI 1.26-1.86 for age ≥70 years) and PD (aHR 1.90, 95% CI 1.29-2.80 for age70 years and aHR 1.47, 95% CI 1.06-2.04 for age ≥70 years) according to subgroups divided by age.Compared to non-AMD participants, AMD patients had higher risk for AD and PD even among those with healthy lifestyle behaviors. Patients with AMD must be closely monitored for possible subsequent development of AD or PD.

Hereditary spastic paraplegia (HSP) refers to a group of neurodegenerative disorders characterized by bilateral weakness, spasticity, and hyperreflexia in the lower limbs. The autosomal dominant HSP (ADHSP) predominantly presents as the pure form, but the clinical profiles and causal genetic variants underlying ADHSP are complex, and many remain unknown. A cohort of 15 Chinese HSP pedigrees (including 35 patients and their 22 relatives) were screened by multiplex ligation-dependent probe amplification (MLPA) or whole-exome sequencing (WES). Neurological assessments were also conducted. The main subtypes of HSP above detected in our cohort were SPG4, SPG3A, and SPG6. Fifteen HSP-inducing mutations were identified, among which six were novel mutations: SPAST c.1277T>C, c.1292G>C, c.1562T>C, and c.1693A>T, NIPA1 c.748A>C, and KIDINS220 c.4448C>G. As expected, the most common presentation of the ADHSP cases was the pure form, manifesting spasticity of lower limbs and hyperreflexia, as well as pyramidal signs. Differing substantially from previous reports for KIDINS220 variants, our study family exhibited autosomal dominant inheritance, and only presented with spastic paraplegia, with no signs of intellectual disability, nystagmus, or obesity. Our work reveals a non-classical spastic paraplegia, intellectual disability, nystagmus, and obesity phenotype for a KIDINS220 mutation, which broadens both the clinical and genetic spectrum for ADHSP. Beyond underscoring the utility of using both MLPA and WES in studies of HSP, our work deepens the scientific understanding of phenotypes for ADHSP and defines new genetic variants to facilitate future diagnoses.

Multi-label image classification problem is one of the most important and fundamental problems in computer vision. In an image with multiple labels, the objects usually locate at various positions with different scales and poses. Moreover, some labels are associated with the entire image instead of a small region. Therefore, both the global and local information are important for classification. To effectively extract and make full use of these information, in this paper, we present a novel deep Dual-stream nEtwork for the muLTi-lAbel image classification task, DELTA for short. As its name indicates, it is composed of two streams, i.e., the Multi-Instance network and the Global Priors network. The former is used to extract the multi-scale class-related local instances features by modeling the classification problem in a multi-instance learning framework. The latter is devised to capture the global priors from the input image as the global information. These two streams are fused by the final fusion layer. In this way, DELTA can extract and make full use of both the global and local information for classification. Extensive experiments on three benchmark datasets, i.e., PASCAL VOC 2007, PASCAL VOC 2012 and Microsoft COCO, demonstrate that DELTA significantly outperforms several state-of-the-art methods. Moreover, DELTA can automatically locate the key image patterns that trigger the labels.

T-cell reduction is an important characteristic of coronavirus disease 2019 (COVID-19), and its immunopathology is a subject of debate. It may be due to the direct effect of the virus on T-cell exhaustion or indirectly due to T cells redistributing to the lungs. HIV/AIDS naturally served as a T-cell exhaustion disease model for recognizing how the immune system works in the course of COVID-19. In this study, we collected the clinical charts, T-lymphocyte analysis, and chest CT of HIV patients with laboratory-confirmed COVID-19 infection who were admitted to Jin Yin-tan Hospital (Wuhan, China). The median age of the 21 patients was 47 years [interquartile range (IQR) = 40–50 years] and the median CD4 T-cell count was 183 cells/μl (IQR = 96–289 cells/μl). Eleven HIV patients were in the non-AIDS stage and 10 were in the AIDS stage. Nine patients received antiretroviral treatment (ART) and 12 patients did not receive any treatment. Compared to the reported mortality rate (nearly 4%–10%) and severity rate (up to 20%–40%) among COVID-19 patients in hospital, a benign duration with 0% severity and mortality rates was shown by 21 HIV/AIDS patients. The severity rates of COVID-19 were comparable between non-AIDS (median CD4 = 287 cells/μl) and AIDS (median CD4 = 97 cells/μl) patients, despite some of the AIDS patients having baseline lung injury stimulated by HIV: 7 patients (33%) were mild (five in the non-AIDS group and two in the AIDS group) and 14 patients (67%) were moderate (six in the non-AIDS group and eight in the AIDS group). More importantly, we found that a reduction in T-cell number positively correlates with the serum levels of interleukin 6 (IL-6) and C-reactive protein (CRP), which is contrary to the reported findings on the immune response of COVID-19 patients (lower CD4 T-cell counts with higher levels of IL-6 and CRP). In HIV/AIDS, a compromised immune system with lower CD4 T-cell counts might waive the clinical symptoms and inflammatory responses, which suggests lymphocyte redistribution as an immunopathology leading to lymphopenia in COVID-19.

Background Aim to identify potential biomarkers to assess therapeutic efficacy for hereditary spastic paraplegias type 5 (SPG5) by investigating the clinical, cerebrospinal fluid (CSF) and magnetic resonance imaging (MRI) features. Methods We performed a cross-sectional study to compare SPG5 patients with age- and sex-matched healthy controls who underwent conventional and quantitative MRI techniques of spinal cord (C1-T9) and brain. SPG5 patients also underwent assessment for clinical status and CSF biomarkers (27-hydroxycholesterol, neurofilament light). We identified a set of markers with standardized effect sizes (|t|> 0.5) to estimate sample sizes for disease progression (disease duration > 14 years vs. ≤ 14 years). Results Seventeen genetically confirmed SPG5 patients (11 men, 6 women; age range, 13–49 years; median disease duration, 14 years) were enrolled. Compared to healthy controls, the total spinal cord area (SCA) of SPG5 patients was reduced particularly at the thoracic levels (cervical levels: 12–27%; thoracic levels 41–60%). Patients did not show significant alterations of brain signal abnormalities or atrophy relative to controls. A total of 10 surrogate markers were selected and a minimum sample size was achieved with the measurement of SCA on T9 (n = 22) much less that what would be required if using clinical disability assessment (n = 124). Conclusions SPG5 patients showed distinct MRI features of spinal cord atrophy without significant brain alterations. Our finding supports the measurements of spinal cord on T9 level as potential endpoint for SPG5 clinical trials. Trial registration ClinicalTrials.gov, NCT04006418. Registered 05 July 2019, https://clinicaltrials.gov/ct2/show/NCT04006418?term=NCT04006418&draw=2&rank=1.

Neurogenetic diseases are neurological conditions with a genetic cause (s). There are thousands of neurogenetic diseases, and most of them are incurable. The development of bioinformatics and elucidation of the mechanism of pathogenesis have allowed the development of gene therapy approaches, which show great potential in treating neurogenetic diseases. Viral vectors delivery, antisense oligonucleotides, gene editing, RNA interference, and burgeoning viroid delivery technique are promising gene therapy strategies, and commendable therapeutic effects in the treatment of neurogenetic diseases have been achieved (Fig. 1). This review highlights a sampling of advances in gene therapies for neurogenetic disorders. Fig. 1 Examples of gene therapy strategies used in the treatment of neurogenetic diseases. The schematic diagram shows different gene therapy approaches used for treating a sampling of neurogenetic disorders, such as ASO therapy, gene editing, gene augmentation, and RNA interference.

NecroX-5 (NX-5) is a cell-permeable necrosis inhibitor with cytoprotective effects. Although it has been reported to inhibit lung and breast cancer metastasis by modulating migration, its therapeutic effect on melanoma metastasis is still unknown. In this study, we examined the anti-metastatic effect of NX-5 on melanoma cell lines and its related therapeutic mechanism. The anti-metastatic effect of NX-5 on melanoma cell lines was determined using a transwell migration assay. We performed a quantitative real-time polymerase chain reaction and western blot analysis to measure changes in the expression of mRNA and protein, respectively, for major mediators of Rho-family GTPases after NX-5 treatment in melanoma cells. In addition, after constructing the 3D melanoma model, the expression of Rho-family GTPases was measured by immunohistochemistry. NX-5 (10 μM and 20 μM) treatment significantly reduced melanoma cell migration (p &lt, 0.01). Additionally, NX-5 (20 μM) treatment significantly decreased the mRNA and protein expression levels of Cdc42, Rac1, and RhoA in melanoma cells compared with the untreated group (p &lt, 0.001 and p &lt, 0.05, respectively). Immunohistochemistry for our 3D melanoma model showed that Cdc42, Rac1, and RhoA were constitutively expressed in the nuclei of melanoma cells of the untreated group, and NX-5 treatment decreased their expression. These results demonstrate that NX-5 can suppress melanoma metastasis by reducing the expression of Rho-family GTPases.

Lumbar spinal stenosis (LSS) is a common neurodegenerative condition. However, how neurogenic claudication develops with severe leg pain has not yet been clearly elucidated. Moreover, cerebrospinal fluid (CSF) physiology at the lumbosacral level is poorly understood because of the difficulties involved in quantification and visualization. Recent studies have suggested that assessment of mitochondrial function in CSF provides an indirect way to assess neurological disorders and an important feature of disease progression. In this study, we assessed the relevance of endogenous extracellular mitochondria in the CSF of rats after LSS. Mitochondrial changes within the CSF were analyzed following LSS at 1 week using flow cytometry. An increase in cell size and number was observed in CSF with LSS, and reactive oxygen species (ROS) levels were also increased within the CSF at 1 week in the LSS group. Elevated mitochondrial ROS and functional changes in the CSF are hallmarks of LSS. The present study is the first to demonstrate that elevated mitochondrial ROS within the CSF is a new index for the early detection of LSS. Moreover, it may represent a potential novel treatment target for LSS.

Background: Human malignant melanoma (MM) is one of the skin cancers with the highest mortality. In this study, we investigated the role of miR-383-5p on human MM cells. Methods: The expression of miR-383-5p was measured by quantitative real-time PCR assay. The cell proliferation, invasion and migration were detected by CCK8, clone formation and transwell assays. Flow cytometry assay was used to detect apoptosis. The binding of miR-383-5p and 3’UTR of CENPF mRNA was indicated by dual-luciferase assays.Results: We found that miR-383-5p inhibited the cells proliferation, migration and invasion, and promoted apoptosis of M14 and A375 cells. Biochemical analysis revealed that the expression of miR-383-5p was negatively correlated with CENPF expression in human MM, and the doul-luciferase report showed that miR-383-5p could effectively bind to the 3’UTR of CENPF. CENPF expression was up-regulated and predicted the prognosis of MM. In addition, high expression of CENPF can effectively remedy the resistance of cell proliferation and vitality caused by miR-383-5p. Conclusion: In conclusion, miR-383-5p acts as a tumor suppressor in human MM by targeting CENPF, suggesting that CENPF may be a potential therapeutic target for human MM.

A bulk-heterojunction (BHJ) structure of organic semiconductor blend is widely used in photon-to-electron converting devices such as organic photodetectors (OPD) and photovoltaics (OPV). However, the impact of the molecular structure on the interfacial electronic states and optoelectronic properties of the constituent organic semiconductors is still unclear, limiting further development of these devices for commercialization. Herein, the critical role of donor molecular structure on OPD performance is identified in highly intermixed BHJ blends containing a small-molecule donor and C60 acceptor. Blending introduces a twisted structure in the donor molecule and a strong coupling between donor and acceptor molecules. This results in ultrafast exciton separation (

Background: Hereditary spastic paraplegias type 5 (SPG5) is an inherited neurodegenerative disease with 27-hydroxycholesterol abnormal accumulation. Imaging and pathologic manifestations remain poorly understood due to the rare incidence. This study reveals the MRI features of SPG5, and aims to investigate a promising imaging diagnostic biomarker for SPG5.Methods: We prospectively recruited SPG5 patients and matched healthy controls from Neurogenetic Diseases Centers of Fujian province in China, clinical and MRI data of whom were collected. Abnormalities of spinal cord and brain were characterized and quantified by conventional and quantitative MRI. Comparisons were conducted between MRI and cerebrospinal fluid (CSF) bioindicators.Results: Seventeen SPG5 patients were enrolled (11 men, 6 women; age range, 13–49 years; median disease duration, 14 years). For the first time, T2 hyperintensities with “+” form (cross sign) in atrophic spinal cord was found among all SPG5 patients. To grade severity of this sign, we set up a scoring scale (cross-sign scores) in cervical spinal cords. Unexpectedly, total cross-sign scores showed a strong positive correlation with disability scale scores (r = 0.687, P = 0.002) and disease duration (r = 0.520, P = 0.032). Although total spinal cord area was reduced (cervical levels: 12-27%; thoracic levels 41-60%), no correlation was found between spinal cord atrophy and disease severity. In CSF, a positive correlation was identified between 27-hydroxycholesterol and neurofilament light (r = 0.468, P = 0.049), although 27-hydroxycholesterol and neurofilament light were unrelated to disease severity.Conclusion: Cross sign of spinal cord was established as a potentially diagnostic biomarker linked to SPG5 that can guide genetic testing and interpret genetic results. Moreover, cross-sign scoring scale is more sensitive than spinal cord area and CSF markers for monitoring SPG5 progress in our research.

Recently, it has been actively conducted to study Network technology based on eMBB, URLLC, mMTC for 5G commercial. Compared to 4G Network, 5G is leading the sensational dissemination and spread of 5G devices, IoT and network infrastructure with outstanding performance differences such as data transmission speed, communication delay time, and connectivity of devices. However, there is a need for a method to select proper radio access technology(RAT) interworking with the legacy network infrastructure (4G/3G/2G) due to the narrow coverage of 5G. There is a need for a way to improve communication service satisfaction through infrastructure and proper and efficient use. In this paper, we propose a method to support efficient mobility of mobile devices for interworking between 5G mobile networks and existing mobile networks (4G/3G/2G), and scenarios for efficiently operating 5G networks and existing networks of global mobile network operators.

Objective: This study aims to explore the association between median nerve-neurophysiological index (NI) and survival of patients with amyotrophic lateral sclerosis (ALS).Methods: A retrospective case series with a prospective follow-up study was performed in 238 patients with ALS. Their clinical profiles and NI were recorded. Kaplan-Meier curves and Cox regression were adopted to perform survival analysis.Results: The median survival time of all ALS cases was 33.0 months. Multivariate analysis showed that older age of onset, shorter diagnostic delay, higher ΔALSFRS-R, and faster progression {NI ≤ 2.15; hazard ratio [HR] = 1.543 [95% confidence interval (CI), 1.136–2.094]} were associated with short survival. NI was correlated with ALSFRS-R at baseline (rs = 0.3153; p < 0.0001) and ALSFRS-R at different time points of follow-up (rs = 0.5127; p < 0.0001). The higher NI slope of decline (> 0.25) showed shorter survival compared with the lower group (≤ 0.25; 34.0 vs. 52.0 months; p = 0.0003). A predictive model was constructed based on the age of onset, diagnostic delay, median nerve NI, and ΔALSFRS-R. The higher predictive score (> 14) showed significantly shorter survival compared with the lower group (≤ 14; HR = 3.907, 95% CI, 2.857–5.342).Conclusion: Median nerve NI and its slope of decline were predictive of survival of ALS.

Studies on monogenic diseases can provide valuable insights into the mechanisms of other neurological disorders, say Wan-Jin Chen and colleagues

Inflammation is an essential biological response that eliminates pathogenic bacteria and repairs tissue after injury. Acute kidney injury (AKI) is associated with systemic and intrarenal inflammation as the inflammatory process decreases renal function and promotes progression to advanced chronic kidney disease. Macrophages are key mediators of the inflammatory response, their activation influences the immune system and may have various effects. Classically activated type I macrophages (M1) produce a variety of pro-inflammatory cytokines at the lesion site. However, anti-inflammatory type II macrophages (M2) are alternatively activated upon exposure to anti-inflammatory cytokines and are associated with wound healing and tissue repair following AKI. Here, we used melittin from bee venom to enhance the polarization of M2 macrophages and promote renal recovery after AKI. Melittin was administered to mice intraperitoneally for 5 days at various concentrations (10, 50, and 100 &micro, g/kg), serum creatinine and blood urea nitrogen (BUN) levels were analyzed 72 h after cisplatin administration to confirm renal dysfunction. Melittin inhibited the cisplatin-induced increase in creatinine and BUN, an indicator of renal dysfunction. The expression of M1 markers (CD16/32) decreased significantly, whereas that of M2 markers (CD206, Arg1nase I) increased after melittin administration. Consistently, tubular necrosis was substantially reduced in melittin-treated mice. Thus, melittin alleviates cisplatin-induced AKI by regulating M2 macrophage expression.

BackgroundPostural instability is one of the most disabling features of spinocerebellar ataxias type 3 (SCA3) and often leads to falls that reduce mobility and functional capacity. This study aimed to quantitatively analyse static and dynamic balance and proprioception function on postural control in patients with SCA3 using the Pro-kin system and optimise rehabilitation programmes for them.MethodsEight-one clinically diagnosed SCA3 patients (38 women, 43 men; aged 39.00 ± 9.66) and 62 healthy controls were studied and evaluated using the Pro-kin system (PK254P, Tecnobody S.r.l, Dalmine, Italy). The measurements included (1) a static balance test in two visual feedback conditions: eyes open (EO) and eyes closed (EC); (2) a dynamic balance test measuring limits of stability (LOS); and (3) a proprioception function test to obtain proprioceptive measurements on a multiaxial balance evaluator for both right and left lower limbs.ResultsCompared to controls, SCA3 patients showed significantly higher values of all static balance outcome variables with eyes open and eyes closed, implying postural instability. SCA3 patients showed significantly higher values in the standard deviation of body sway along the medio-lateral (ML) axis and in the velocity of body sway along the anterior-posterior (AP) axis. The overall scores and the scores for all eight LOS components were significantly lower in the SCA3 patients than in the controls. The mean values of AP index (API), ML index (MLI), Stability index (SI) and average trace error (ATE) were significantly greater in SCA3 patients compared to HC subjects, while API showed a trend toward higher values.ConclusionsSCA3 patients have a significant postural control disorder, and are likely to fall on the AP plane and prefer performing postural adjustments in the ML direction; a decreased proprioception function in the knee and ankle is also evident. Visual cues and proprioception should be emphasized in balance rehabilitation training. Attention should also be paid to improve muscle strength and range of motion.Trial registrationThe Chinese clinical test registration center. ChiCTR1800020133. Registered 15 december 2018 - Retrospectively registered, http://www.chictr.org.cn/showprojen.aspx?proj=33950

In the field of computer-aided recognition, edge feature is one of the key factors to determine recognition performance. Comparing to an optical image, since sonar image via acoustic wave is easily influenced by underwater environments such as particle density, temperature, and current, edge information should be boosted. Some image preprocessing techniques based on transform domain such as wavelet and curvelet may be good candidates but conventional methods show not only the possibility of enhancing edge features but also the limitation due to the absence of consideration to the edge direction. This study proposes an improved edge enhancement method based on curvelet transform (CVT), which is able to find out edge direction. The proposed method (PM) calculates the maximum value by ridgelet coefficients on each angular line, derived from the sub-step of the CVT, and the real edge direction is determined by local maxima selection after finding the azimuth of this value. In addition, selective sharpening is performed according to the feature information of edge. Experimental results have shown that the PM is comparable with conventional methods in terms of edge intensity, recognition rate, and peak signal-to-noise ratio.

Background: Spinocerebellar ataxia type 3 (SCA3) is an inherited form of ataxia that leads to progressive neurodegeneration. Fatigue is a common non-motor symptom in SCA3 and other neurodegenerative diseases, such as Parkinson's disease (PD) and amyotrophic lateral sclerosis (ALS). Although risk factors to fatigue in these diseases have been thoroughly studied, whether or not fatigue can affect clinical phenotypes has yet to be investigated. Methods: Ninety-one molecularly confirmed SCA3 patients and 85 age- and sex-matched controls were recruited for this study. The level of fatigue was measured using the 14-item Fatigue Scale (FS-14), and the risk factors to fatigue and how fatigue correlates with clinical phenotypes were studied using multivariable linear regression models. Results: We found that the severity was significantly higher in the SCA3 group than in the control group (9.30 ± 3.04% vs. 3.94 ± 2.66, P = 0.000). Daytime somnolence (β = 0.209, P = 0.002), severity of ataxia (β = 0.081, P = 0.006), and poor sleep quality (β = 0.187, P = 0.037) were found to have a positive relationship with fatigue. Although fatigue had no relationship with age at onset or ataxic progression, we found that it did have a positive relationship with the severity of ataxia (β = 7.009, P = 0.014). Conclusions: The high level of fatigue and the impact of fatigue on the clinical manifestation of SCA3 patients suggest that fatigue plays a large role in the pathogenesis of SCA3, thus demonstrating the need for intervention and treatment options in this patient cohort.

As mobile devices become more affordable, sustainable and portable, they have become kinds of personal ecosystem to people in the 21st century, and they bring unprecedented educational opportunities to students of all socio-economic levels. This research explored the potential use of mobile devices in selected public senior high schools in the City of Manila, Philippines. A total of 152 students from a couple of schools have participated in this study. It was found that the majority of the participants have some form of mobile devices and internet access as they were used for a variety of learning activities outside the classroom settings. However, substantial digital inequalities also exist among public schools in the City of Manila. Overall, the findings indicate that mobile devices have shown potential to be adopted in existing public senior high schools, and there is a need to update policy and curricula to respond to the mobile era. https://doi.org/10.26803/ijlter.17.4.7

Background Amyotrophic lateral sclerosis (ALS) is a devastating motor neuron disease characterized by substantial clinical and genetic heterogeneity. Thus far, only a few TARDBP-ALS families have been reported in China, and no mutation analysis has been reported in south-eastern China. Methods Seven index cases from ALS families negative for SOD1 and FUS mutations were screened by Sanger sequencing for TARDBP gene exons 2-6. TARDBP exon 6 was analysed in 215 sporadic ALS patients. Results Two TARDBP mutations in exon 6 (p.M337 V and p.G348C) were identified in 5 unrelated families. Four of these 5 families carried the same p.M337 V mutation (family 1II3, family 2II6, family 3II4, and family 4II4), and the p.G348C mutation was identified in family 5 (II5). Among the 215 sporadic patients, only a single nucleotide polymorphism (p.A366A) was detected in 5 patients, and no responsible mutation was identified. Among the TARDBP-linked familial ALS patients, the average age of onset was 57.0 ± 4.7 years, and a trend towards higher rates of bulbar (50.0%, 6/12) onset and upper limb (41.7%, 5/12) onset than lower rates of limb onset (8.3%, 1/12) was observed. Furthermore, ALS patients with TARDBP mutations showed a benign disease course, and the average survival was 106.5 ± 41.8 months (n = 8). Conclusions We found a high frequency of the TARDBP p.M337 V mutation in familial ALS in south-eastern China. The TARDBP-linked ALS patients showed a benign disease course and prolonged survival. Electronic supplementary material The online version of this article (10.1186/s12883-018-1028-1) contains supplementary material, which is available to authorized users.

Summary: Background: Facioscapulohumeral muscular dystrophy type 1 (FSHD1) is a rare disease, which is often underdiagnosed due to its heterogeneous presentations and complex molecular genetic basis, leading to a lack of population-based epidemiology data, especially of prevalence and disease progression. Methods: Fujian Neuromedical Centre (FNMC) is a diagnosis centre for clinical-genetic FSHD in China, and the only one employing pulsed-field gel electrophoresis (PFGE)-based Southern blotting for all FSHD1 genetic tests. Three sources distributed across all six spatial zones in China, were used to obtain information regarding FSHD1 events, namely, FNMC, Genetic and Myopathy Group (branches of the Neurology Society of the Chinese Medical Association), and “FSHD-China” (an organization supported by FSHD patients). During 2001-2020, all genetically-confirmed FSHD1 from China were registered in FNMC. Follow-up was conducted in the 20-year period to obtain data on disease progression, which was mainly described in terms of independent ambulation loss. Findings: Of the 1,744 FSHD1 genetic tests (total test number 1,802) included in the analysis, 997 (57.2%) patients from 620 families were diagnosed with FSHD1. The estimated prevalence of genetically-confirmed FSHD1 in China is 0.75 per million (95% confidence interval [CI], 0.70-0.79) during 2001-2020, with 0.78 (95% CI, 0.72-0.85) in males and 0.71 (95% CI, 0.65-0.78) in females. The estimated prevalence increased from 0.22 (95% CI, 0.19-0.26) per million in 2001-2015 to 0.53 (95% CI, 0.49-0.57) per million in 2016-2020 (p < 0.001). The prevalence in Fujian province was 7.10 per million, 4.66 per million, and 2.44 per million, during 2001-2020, 2001-2015, and 2016-2020, respectively. Among the 861 symptomatic plus asymptomatic patients of the total 997 patients, the median onset age at first-ever muscle weakness was 16 years of age (range 1-81); the median number of contracted D4Z4 repeats was 5 units (range 1-9); the median 4qA-allele-specific methylation level was 41% (range 14%-69%). Of the 977 symptomatic patients followed-up during 2001-2020, 117 patients (12.0%) lost independent ambulation. The expected duration from onset of first-ever muscle weakness to onset of independent ambulation loss was 40 years. The group with loss of independent ambulation had a smaller number of contracted D4Z4 repeats (p < 0.001) and had an earlier onset age of first-ever muscle weakness (p < 0.001) compared to the group without loss of independent ambulation. Interpretation: Our research captures the largest genetically-confirmed FSHD1 population worldwide, to calculate its prevalence of 0.75 per million in China from 2001 to 2020. Approximately 12.0% of symptomatic plus asymptomatic patients of FSHD1 will lose independent ambulation in 40 years from onset of first-ever muscle weakness. Funding: This work has been supported by the grants (U2005201, 81870902, N.W.) and (81974193, 81671237, Z.Q.W.) from the National Natural Science Foundation of China; Joint Funds for the Innovation of Science and Technology of Fujian Province (2018Y9082) (N.W.), and the Key Clinical Specialty Discipline Construction Program of Fujian (N.W.).

Background: Progressive myoclonus epilepsies (PMEs) comprise a group of rare genetic disorders characterized by action myoclonus, epileptic seizures, and ataxia with progressive neurologic decline. Due to clinical and genetic heterogeneity of PMEs, it is difficult to decide which genes are affected. The aim of this study was to report an action myoclonus with or without renal failure syndrome (EPM4) family and summarize the clinical and genetic characteristics of all reported EPM4 patients. Methods: In the present study, targeted next-generation sequencing (NGS) was applied to screen causative genes in a Chinese PME family. The candidate variant was further confirmed by cosegregation analysis and further functional analysis, including the reverse transcription polymerase chain reaction and Western blot of the proband’s muscle. Moreover, literature data on the clinical and mutational features of all reported EPM4 patients were reviewed. Results: The gene analysis revealed a novel homozygous splicing mutation (c.995-1G>A) of the SCARB2 gene in two brothers. Further functional analysis revealed that this mutation led to loss function of the SCARB2 protein. The classification of the candidate variant, according to the American College of Medical Genetics and Genomics standards and guidelines and functional analysis, was pathogenic. Therefore, these two brothers were finally diagnostically confirmed as EPM4. Conclusions: These present results suggest the potential for targeted NGS to conduct a more rapid and precise diagnosis for PME patients. A literature review revealed that mutations in the different functional domains of SCARB2 appear to be associated with the phenotype of EPM4. Key words: Progressive Myoclonus Epilepsies; Progressive Myoclonus Epilepsy with or without Renal Failure; SCARB2 Gene; Targeted Next-Generation Sequencing

The development of clinical trials for Duchenne muscular dystrophy (DMD) in China faces many challenges due to limited information about epidemiological data, natural history and clinical management. To provide these detailed data, we developed a comprehensive database based on registered DMD patients from South China and analysed their clinical and mutational characteristics. The database included DMD registrants confirmed by clinical presentation, family history, genetic detection, prognostic outcome, and/or muscle biopsy. Clinical data were collected by a registry form. Mutations of dystrophin were detected by multiplex ligation-dependent probe amplification (MLPA) and Sanger sequencing. Currently, 132 DMD patients from 128 families in South China have been registered, and 91.7% of them were below 10 years old. In mutational detection, large deletions were the most frequent type (57.8%), followed by small deletion/insertion mutations (14.1%), nonsense mutations (13.3%), large duplications (10.9%), and splice site mutations (3.1%). Clinical analysis revealed that most patients reported initial symptoms between 1 and 3 years of age, but the diagnostic age was more frequently between 6 and 8 years. 81.4% of patients were ambulatory. Baseline cardiac assessments at diagnosis were conducted in 39.4% and 29.5% of patients by echocardiograms and electrocardiograms, respectively. Only 22.7% of registrants performed baseline respiratory assessments. A small numbers of patients (20.5%) were treated with glucocorticoids. 13.3% of patients were eligible for stop codon read-through therapy, and 48.4% of patients would potentially benefit from exon skipping. The top five exon skips applicable to the largest group of registrants were skipping of exons 51 (14.8% of total mutations), 53 (12.5%), 45 (7.0%), 55 (4.7%), and 44 (3.9%). In conclusion, our database provided information on the natural history, diagnosis and management status of DMD in South China, as well as potential molecular therapies suitable for these patients. This comprehensive database will promote future experimental therapies in China.

BACKGROUND Pain and adhesion are problematic issues after surgery. Lidocaine has analgesics and anti-inflammatory properties, and poloxamer/alginate/CaCl2 (PACM) is a known antiadhesive agent. We hypothesized that the novel combination of lidocaine as chemical barrier and PACM as physical barrier would be beneficial for both postoperative pain and adhesion. The purpose of this study was to investigate the effects of lidocaine-loaded PACM in a rat model of incisional pain. Primary outcome was to evaluate between-group differences for the mechanical withdrawal threshold (MWT) measured by von Frey filament in various concentrations of lidocaine-loaded PACM applied, PACM applied, and sham-operated groups. METHODS Male Sprague-Dawley rats were used for the postoperative pain model. After plantar incision and adhesion formation, 0.5%, 1%, 2%, and 4% lidocaine-loaded PACM, PACM only, nothing, and 4% lidocaine only were applied at the incision site in groups PL0.5, PL1, PL2, PL4, P, S, and L4, respectively. MWT using a von Frey filament and serum levels of tumor necrosis factor-α, interleukin (IL)-1β, IL-6, and high-sensitivity C-reactive protein were measured. Rats were euthanized 2 weeks after surgery, and inflammation and fibrosis were assessed with microscopy. Data were analyzed using the Kruskal-Wallis test, multivariate analysis of variance, and linear mixed-effect model. To compare MWT at each time point, analysis of variance with Bonferroni correction was used. RESULTS Multivariate analysis of variance showed that 4% lidocaine-loaded PACM significantly raised the MWT up to 6 and 8 hours after surgery compared with lidocaine-unloaded groups S and P, respectively; 2% lidocaine-loaded PACM significantly increased the MWT at 4 hours after surgery compared with groups S and C. Linear mixed-effect model showed that the MWT (estimated difference in means [95% confidence interval]) was significantly increased in groups PL2 and PL4 (6.58 [2.52-10.63], P = .002; 11.46 [7.40-15.51], P < .001, respectively) compared with group P. Inflammation and fibrosis seen on microscopic evaluation were significantly decreased in groups PL2 and PL4 compared with group S. Four percent of lidocaine only showed a significant reduction in inflammation. Serum levels of tumor necrosis factor-α, IL-1β, IL-6, and high-sensitivity C-reactive protein were decreased in lidocaine-loaded groups compared with group S or P at 1, 2, and 48 hours, and 2 weeks after surgery, respectively. CONCLUSIONS Lidocaine-loaded PACM reduced postoperative pain, and lidocaine strengthened the antiadhesive effect of PACM.

ADAM17, a disintegrin and metalloproteinase 17, is a transmembrane metalloproteinase that regulates bioavailability of multiple membrane-bound proteins via ectodomain shedding. ADAM17 activity was shown to contribute to a number of vascular pathologies, but its role in the context of diabetic retinopathy (DR) is not determined. We found that expression and enzymatic activity of ADAM17 are upregulated in human diabetic postmortem retinas and a mouse model of streptozotocin-induced diabetes. To further investigate the contribution of ADAM17 to vascular alterations associated with DR, we used human retinal endothelial cells (HREC) treated with ADAM17 neutralizing antibodies and exposed to glucidic stress and streptozotocin-induced endothelial ADAM17 knockout mice. Evaluation of vascular permeability, vascular inflammation, and oxidative stress was performed. Loss of ADAM17 in endothelial cells markedly reduced oxidative stress evidenced by decreased levels of superoxide, 3-nitrotyrosine, and 4-hydroxynonenal and decreased leukocyte-endothelium adhesive interactions in vivo and in vitro. Reduced leukostasis was associated with decreased vascular permeability and was accompanied by downregulation of intercellular adhesion molecule-1 expression. Reduction in oxidative stress in HREC was associated with downregulation of NAD(P)H oxidase 4 (Nox4) expression. Our data suggest a role for endothelial ADAM17 in DR pathogenesis and identify ADAM17 as a potential new therapeutic target for DR.

Background: Hereditary spastic paraplegia type 5 (SPG5) is an ultra-rare neurogenetic axon-degenerative disease. The absence of treatment to prevent disease progression represents a major unmet clinical need. With a greater understanding of the pathophysiological basis of SPG5, opportunities have emerged for providing a targeted mechanistic therapy. The aims of this preliminary study were to investigate the efficacy of a PCSK9 inhibitor, Evolocumab, as a cholesterol-lowering therapy for reducing the accumulation of neurotoxic oxysterols and to evaluate the effects on axonal degeneration. Methods: This was as an open-label, evaluator-blind, single-center pilot study in which 23 SPG5 patients each received a single subcutaneous injections of 420 mg Evolocumab. Clinical data, CSF and blood were collected for analysis at enrollment and subsequent day 30. Induced pluripotent stem cells (iPSCs) were generated from the fibroblasts of a SPG5 patient to assess the mechanism of PCSK9 inhibitor’s effect on treatment. Findings: This trial is the largest sample-size prospective study among any treatment trial for SPG5. In this relatively homogeneous group of SPG5 patients (96% carried the same known nonsense mutation c.334 C>T; the median age was 34 years; disease duration was 16 years), we found that PCSK9 inhibitor significantly lowered levels of the toxic metabolite 27-hydroxycholesterol (27-OHC) in plasma (median (IQR), 589(487-644) vs. 396(348-468) ng/ml , P < 0.001). CSF 27-OHC decreased in 12 (71%) patients with a median reduction by 11% from the median 10 ng/ml before treatment to 8.3 ng/ml after treatment (P = 0.012). Most importantly, axonal degeneration, assessed by using neurofilament light (NFL) as a quantitative biomarker, receded at 30 days after single-dose Evolocumab treatment. Additionally, using iPSC-derived motor neurons, this study also showed that PCSK9 inhibitor had anti-apoptosis activity in SPG5 patients. Interpretation: The potential biological activity of cholesterol modulation for SPG5 patients, that is, alleviation of damage to axons from the effects of neurotoxic oxysterol, as well as the absence of adverse effects associated with the use of PCSK9 inhibitor therapy documented here deserves, in fact urges, full evaluation by well-designed long-term clinical trials. Trial Registration: This study is registered with ClinicalTrials.gov, number: NCT01892345. Funding Statement: This work has been supported by grants U1905210 (W.-J.C.), 81771230(W.-J.C.) and 81801130 (X.L.) from the National Natural Science Foundation of China, Joint Funds for the Innovation of Science and Technology of Fujian Province (2017Y9094) (W.-J.C.) and (2018Y9082) (N.W.), the Natural Science Foundation of Fujian Province (2019J02010) (W.-J.C.) and (2019J05076) (X.L.), the Key Clinical Specialty Discipline Construction Program of Fujian (N.W.). Declaration of Interests: All authors report no conflict of interest. Fujian medical university school of public health have received consultant fees as statistician to perform the data analysis. Ethics Approval Statement: The study protocol and informed consent procedures were approved by the institutional review board. Written informed consent was provided by the patients and their health care proxies.

As organic photodetectors with less than 1 μm pixel size are in demand, a new way of enhancing the sensitivity of the photodetectors is required to compensate for its degradation due to the reduction in pixel size. Here, we used Ag nanoparticles coated with SiOxNy as a light-absorbing layer to realize the scale-down of the pixel size without the loss of sensitivity. The surface plasmon resonance appeared at the interface between Ag nanoparticles and SiOxNy. The plasmon resonance endowed the organic photodetector with boosted photon absorption and external quantum efficiency. As the Ag nanoparticles with SiOxNy are easily deposited on ITO/SiO2, it can be adapted into various organic color image sensors. The plasmon-supported organic photodetector is a promising solution for realizing color image sensors with high resolution below 1 μm.

Background Accurate clinical staging of tumors with a small solid portion is essential for developing an appropriate treatment plan. This study evaluated predictive factors for lymph node (LN) metastasis in patients with clinical stage I part-solid lung adenocarcinoma. Methods Medical records of patients with clinical stage I part-solid adenocarcinoma who underwent anatomic pulmonary resection with systematic node evaluation between January 2009 and June 2018 were retrospectively reviewed. To identify predictive factors for LN metastasis, univariate and multivariable logistic regression analyses were performed. Results Among the 593 patients in this study, the overall prevalence of LN metastasis was 3.7% (n = 22), which included 3.0% (n = 18) of patients with N1 LN metastasis and 1.5% (n = 9) of patients with N2 LN metastasis. Combined N1 and N2 nodal involvement was observed in 5 patients. Nodal metastasis was not observed in tumors with a solid portion sized 1.1 cm or smaller. The nodal metastasis rates in cT1b, cT1c, and cT2a tumors were 5.5% (13 of 237), 7.1% (6 of 84), and 13.6% (3 of 22), respectively. According to the multivariable analysis, predictive factors included the size of the solid portion (P = .015) and the high maximum standardized uptake value (SUVmax) of the primary tumor (P = .044). Conclusions Large solid portion and high SUVmax of the primary tumor were predictive factors of LN metastasis in patients with clinical stage I part-solid lung adenocarcinoma. Systematic LN evaluation should be performed, especially in those who have a large solid portion and high SUVmax of the primary tumor.

We explored prognostic roles of circulating microRNAs (miRs) in multiple myeloma (MM) treated with autologous stem cell transplantation (ASCT) following induction chemotherapy. In part I of the study (n = 40), we identified a decreasing dynamics of circulating miR-193a-5p expression from diagnosis to pre-ASCT. In patients who experienced early relapse within one year post ASCT (n = 9) these patterns were distinctive compared to those without early relapse in a 1:2 matched cohort (n = 18). In part II (n = 90), multivariate analyses showed that the International Staging System score and miR-193a-5p expression before ASCT were independent prognostic factors. Conclusively, expression of circulating miR-193a-5p before ASCT could be a prognostic biomarker for transplant-eligible MM.