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BackgroundHuman immunodeficiency virus (HIV)-associated sensory neuropathy is a common neurological complication of HIV infection affecting up to 30% of HIV-positive individuals. However, the exact neuropathological mechanisms remain unknown, which hinders our ability to develop effective treatments for HIV-related neuropathic pain (NP). In this study, we tested the hypothesis that inhibition of proinflammatory factors with overexpression of interleukin (IL)-10 reduces HIV-related NP in a rat model.MethodsNP was induced by the application of recombinant HIV-1 envelope protein gp120 into the sciatic nerve. The hindpaws of rats were inoculated with nonreplicating herpes simplex virus (HSV) vectors expressing anti-inflammatory cytokine IL-10 or control vector. Mechanical threshold was tested using von Frey filaments before and after treatments with the vectors. The mechanical threshold response was assessed over time using the area under curves. The expression of phosphorylated p38 mitogen-activated kinase, tumor necrosis factor-α, stromal cell-derived factor-1α, and C-X-C chemokine receptor type 4 in both the lumbar spinal cord and the L4/5 dorsal root ganglia (DRG), was examined at 14 and 28 days after vector inoculation using Western blots.ResultsWe found that in the gp120-induced NP model, IL-10 overexpression mediated by the HSV vector resulted in a significant elevation of the mechanical threshold that was apparent on day 3 after vector inoculation compared with the control vector (P < 0.001). The antiallodynic effect of the single HSV vector inoculation expressing IL-10 lasted >28 days. The area under curve in the HSV vector expressing IL-10 was increased compared with that in the control vector (P < 0.0001). HSV vectors expressing IL-10 reversed the upregulation of phosphorylated p38 mitogen-activated kinase, tumor necrosis factor-α, stromal cell-derived factor-1α, and C-X-C chemokine receptor type 4 expression at 14 and/or 28 days in the DRG and/or the spinal dorsal horn.ConclusionsOur studies demonstrate that blocking the signaling of these proinflammatory molecules in the DRG and/or the spinal cord using the HSV vector expressing IL-10 is able to reduce HIV-related NP. These results provide new insights on the potential mechanisms of HIV-associated NP and a proof of concept for treating painful HIV sensory neuropathy with this type of gene therapy.

BackgroundHIV-associated sensory neuropathy affects over 50% of HIV patients and is a common peripheral nerve complication of HIV infection and highly active antiretroviral therapy (HAART). Evidence shows that painful HIV sensory neuropathy is influenced by neuroinflammatory events that include the proinflammatory molecules, MAP Kinase, tumor necrosis factor-α (TNFα), stromal cell-derived factor 1-α (SDF1α), and C-X-C chemokine receptor type 4 (CXCR4). However, the exact mechanisms of painful HIV sensory neuropathy are not known, which hinders our ability to develop effective treatments. In this study, we investigated whether inhibition of proinflammatory factors reduces the HIV-associated neuropathic pain state.ResultsNeuropathic pain was induced by peripheral HIV coat protein gp120 combined with 2',3'-dideoxycytidine (ddC, one of the nucleoside reverse transcriptase inhibitors (NRTIs)). Mechanical threshold was tested using von Frey filament fibers. Non-replicating herpes simplex virus (HSV) vectors expressing interleukin 10 (IL10) were inoculated into the hindpaws of rats. The expression of TNFα, SDF1α, and CXCR4 in the lumbar spinal cord and L4/5 dorsal root ganglia (DRG) was examined using western blots. IL-10 expression mediated by the HSV vectors resulted in a significant elevation of mechanical threshold. The anti-allodynic effect of IL-10 expression mediated by the HSV vectors lasted more than 3 weeks. The area under the effect-time curves (AUC) in mechanical threshold in rats inoculated with the HSV vectors expressing IL-10, was increased compared with the control vectors, indicating antinociceptive effect of the IL-10 vectors. The HSV vectors expressing IL-10 also concomitantly reversed the upregulation of p-p38, TNFα, SDF1α, and CXCR4 induced by gp120 in the lumbar spinal dorsal horn and/or the DRG at 2 and/or 4 weeks.ConclusionThe blocking of the signaling of these proinflammatory molecules is able to reduce HIV-related neuropathic pain, which provide a novel mechanism-based approach to treating HIV-associated neuropathic pain using gene therapy.

Based on a sample of Chinese ChiNext (Growth Enterprise Market) firms during their initial public offerings (IPOs) from 2009 to 2019, this study explores whether these firms engage in sales growth management and examines its economic consequences. We provide evidence that ChiNext firms tend to manage their sales growth to influence issuance prices during IPOs. Further, the study identifies several indicators that suggest growth‐managing firms engage in more aggressive and riskier promotional strategies, such as longer turnover days of receivables, lower gross profit margins and higher allowance ratios for doubtful accounts. The study also finds that growth‐managing firms are more likely to have higher price‐to‐earnings ratios, offer prices, overfund ratios, first‐day closing prices and a higher percentage of positive posts, suggesting that these firms aim to inflate their growth to attract more funds from financial markets by influencing investors' expectations. Additionally, we find a negative relationship between sales management and post‐IPO stock returns, indicating that investors cannot effectively identify sales management by ChiNext IPO firms. Cross‐sectional analysis also shows that growth‐managing ChiNext IPO firms are likely to have depressed post‐IPO performance, whereas the market intermediary (brokers, auditors and asset appraisal institutions) with a good reputation helps to alleviate future performance reversals. [ABSTRACT FROM AUTHOR]

With the rapid development of image registration technology, it is being widely used in the fields of medical image processing, remote sensing image analysis, computer vision, and others. Image registration involves two or more images that contain the same object that are obtained under different conditions. Geometric mapping between images is realized by spatial geometric transformation, so that the points in one image can be related to their corresponding points in the other. Compared with rigid transformations, non-rigid transformations usually have severe local distortions and obvious nonlinear characteristics. So, it is difficult to describe non-rigid transformations using a unified transformation model. For this reason, non-rigid image registration has always been an issue and a source of difficulty in the field of computer vision. To solve this problem, an improved optical-flow-model algorithm was proposed to more accurately estimate the optical flow field. First, the original variational optical flow model was improved. To prevent blurring and preserve the edge and detail features of images, a new anisotropic regular term was proposed to replace the original homologous diffusion term. Then, to remove optical flow outliers, a non-local smoothness term was introduced that contained neighborhood information. Moreover, a weight function that combines image-structure and optical-flow information was added to reduce the loss of detail caused by over-smoothing and to improve robustness. Finally, to solve the displacement field and realize the automatic registration of non-rigid images, an alternating minimization method and pyramid hierarchical iteration strategy were utilized. To verify the effectiveness of the proposed algorithm, subjective and objective evaluation values such as the peak signal-to-noise ratio (PSNR) and normalized mutual information (NMI) were adopted to analyze the registration results. Compared with state-of-the-art methods, experimental results reveal the robustness and ideal registration effects of the proposed method on different types of non-rigid images.