Reduced spinal microglial activation and neuropathic pain after nerve injury in mice lacking all three nitric oxide synthases

<p>Abstract</p> <p>Background</p> <p>Several studies have investigated the involvement of nitric oxide (NO) in acute and chronic pain using mice lacking a single NO synthase (NOS) gene among the three isoforms: neuronal (nNOS), inducible (iNOS) and endothelial (eNOS). However, the precise role of NOS/NO in pain states remains to be determined owing to the substantial compensatory interactions among the NOS isoforms. Therefore, in this study, we used mice lacking all three NOS genes (<it>n/i/eNOS^-/-</it>mice) and investigated the behavioral phenotypes in a series of acute and chronic pain assays.</p> <p>Results</p> <p>In a model of tissue injury-induced pain, evoked by intraplantar injection of formalin, both <it>iNOS^-/-</it>and <it>n/i/eNOS^-/-</it>mice exhibited attenuations of pain behaviors in the second phase compared with that in wild-type mice. In a model of neuropathic pain, nerve injury-induced behavioral and cellular responses (tactile allodynia, spinal microglial activation and Src-family kinase phosphorylation) were reduced in <it>n/i/eNOS^-/-</it>but not <it>iNOS^-/-</it>mice. Tactile allodynia after nerve injury was improved by acute pharmacological inhibition of all NOSs and nNOS. Furthermore, in MG-5 cells (a microglial cell-line), interferon-γ enhanced NOSs and Mac-1 mRNA expression, and the Mac-1 mRNA increase was suppressed by L-NAME co-treatment. Conversely, the NO donor, sodium nitroprusside, markedly increased mRNA expression of Mac-1, interleukin-6, toll-like receptor 4 and P2X4 receptor.</p> <p>Conclusions</p> <p>Our results provide evidence that the NOS/NO pathway contributes to behavioral pain responses evoked by tissue injury and nerve injury. In particular, nNOS may be important for spinal microglial activation and tactile allodynia after nerve injury.</p

Radioprotection by p53 Regulatory Agents

Radiation damage to normal tissues is one of the most serious concerns in radiation therapy, and the tolerance dose of the normal tissues limits the therapeutic dose to the patients. p53 is well known as a transcription factor closely associated with radiation-induced cell death. We recently demonstrated the protective effects of several p53 regulatory agents against low-LET X- or γ-ray-induced damage. Although it was reported that high-LET heavy ion radiation (>85 keV/μm) could cause p53-independent cell death in some cancer cell lines, whether there is any radioprotective effect of the p53 regulatory agents against the high-LET radiation injury in vivo is still unclear. In the present study, we verified the efficacy of these agents on bone marrow and intestinal damages induced by high-LET heavy-ion irradiation in mice. We used a carbon-beam (14 keV/μm) that was shown to induce a p53-dependent effect and an iron-beam (189 keV/μm) that was shown to induce a p53-independent effect in a previous study. Vanadate significantly improved 60-day survival rate in mice treated with total-body carbon-ion (p < 0.0001) or iron-ion (p < 0.05) irradiation, indicating its effective protection of the hematopoietic system from radiation injury after high-LET irradiation over 85 keV/μm. 5CHQ also significantly increased the survival rate after abdominal carbon-ion (p < 0.02), but not iron-ion irradiation, suggesting the moderate relief of the intestinal damage. These results demonstrated the effectiveness of p53 regulators on acute radiation syndrome induced by high-LET radiation

AVIDa-hIL6: A Large-Scale VHH Dataset Produced from an Immunized Alpaca for Predicting Antigen-Antibody Interactions

Antibodies have become an important class of therapeutic agents to treat human diseases. To accelerate therapeutic antibody discovery, computational methods, especially machine learning, have attracted considerable interest for predicting specific interactions between antibody candidates and target antigens such as viruses and bacteria. However, the publicly available datasets in existing works have notable limitations, such as small sizes and the lack of non-binding samples and exact amino acid sequences. To overcome these limitations, we have developed AVIDa-hIL6, a large-scale dataset for predicting antigen-antibody interactions in the variable domain of heavy chain of heavy chain antibodies (VHHs), produced from an alpaca immunized with the human interleukin-6 (IL-6) protein, as antigens. By leveraging the simple structure of VHHs, which facilitates identification of full-length amino acid sequences by DNA sequencing technology, AVIDa-hIL6 contains 573,891 antigen-VHH pairs with amino acid sequences. All the antigen-VHH pairs have reliable labels for binding or non-binding, as generated by a novel labeling method. Furthermore, via introduction of artificial mutations, AVIDa-hIL6 contains 30 different mutants in addition to wild-type IL-6 protein. This characteristic provides opportunities to develop machine learning models for predicting changes in antibody binding by antigen mutations. We report experimental benchmark results on AVIDa-hIL6 by using neural network-based baseline models. The results indicate that the existing models have potential, but further research is needed to generalize them to predict effective antibodies against unknown mutants. The dataset is available at https://avida-hil6.cognanous.com

A nationwide, multi-center, retrospective study of symptomatic small bowel stricture in patients with Crohn\u27s disease.

BACKGROUND:Small bowel stricture is one of the most common complications in patients with Crohn\u27s disease (CD). Endoscopic balloon dilatation (EBD) is a minimally invasive treatment intended to avoid surgery; however, whether EBD prevents subsequent surgery remains unclear. We aimed to reveal the factors contributing to surgery in patients with small bowel stricture and the factors associated with subsequent surgery after initial EBD.METHODS:Data were retrospectively collected from surgically untreated CD patients who developed symptomatic small bowel stricture after 2008 when the use of balloon-assisted enteroscopy and maintenance therapy with anti-tumor necrosis factor (TNF) became available.RESULTS:A total of 305 cases from 32 tertiary referral centers were enrolled. Cumulative surgery-free survival was 74.0% at 1 year, 54.4% at 5 years, and 44.3% at 10 years. The factors associated with avoiding surgery were non-stricturing, non-penetrating disease at onset, mild severity of symptoms, successful EBD, stricture length < 2 cm, and immunomodulator or anti-TNF added after onset of obstructive symptoms. In 95 cases with successful initial EBD, longer EBD interval was associated with lower risk of surgery. Receiver operating characteristic analysis revealed that an EBD interval of ≤ 446 days predicted subsequent surgery, and the proportion of smokers was significantly high in patients who required frequent dilatation.CONCLUSIONS:In CD patients with symptomatic small bowel stricture, addition of immunomodulator or anti-TNF and smoking cessation may improve the outcome of symptomatic small bowel stricture, by avoiding frequent EBD and subsequent surgery after initial EBD

Fabrication of Magnetically Driven Microvalve Arrays Using a Photosensitive Composite

Microvalves play an important role in fluid control in micro total analysis systems (µTAS). Previous studies have reported complex fabrication processes for making microvalve elements in a channel. Hence, there is a need for a simpler microvalve fabrication method for achieving throughput improvement and cost reduction in µTAS. In this study, we propose a simple fabrication method for a magnetically driven microvalve array using a photosensitive composite. The composite was prepared by mixing a photoresist and magnetic particles of pure iron. The simple fabrication process was performed by using a laminating layer composed of a sacrificial part and the composite in a channel. The microvalve elements were fabricated by one-step photolithography using the processability of the sacrificial layer and composite. Further, we demonstrated the magnetic driving property of the fabricated microvalve array device. Compared to devices containing non-driving microvalves, the flow rate was decreased by 50%, and the pressure difference between the inlet and outlet increased by up to 4 kPa with increase in driving microvalve elements. These results imply that our proposed device could be useful for practical µTAS applications

Review of Radiological Parameters, Imaging Characteristics, and Their Effect on Optimal Treatment Approaches and Surgical Outcomes for Cervical Ossification of the Posterior Longitudinal Ligament

Determining the optimal surgical method for cervical ossification of the posterior longitudinal ligament (OPLL) is challenging. The surgical indication should be made based on not only radiological findings, but also the patient’s age, preoperative neurological findings, social background, activities of daily life, and the presence or absence of comorbid diseases. Anterior resection for OPLL with or without wide corpectomy and fusion, posterior decompression with or without relatively long fusion, or anterior and posterior combined surgery may be considered. When evaluating the clinical condition of patients with cervical OPLL before surgery, various radiological parameters should be carefully considered, including the number of spinal segments involved, the cervical alignment or tilt angle, the relationship between OPLL and the C2–7 line (termed the “K-line”), the occupying ratio of OPLL, and the involvement of dural ossification. The objective of this article is to review the radiological parameters in current use for deciding upon the optimal surgical strategy and for predicting surgical outcomes, focusing on cervical OPLL

Complex Revision Surgery for Cervical Deformity or Implant Failure

Postoperative cervical deformity sometimes occurs in the short or long term after primary surgery for cervical disorders related to the degenerative aging spine, neoplastic etiologies, hemodialysis, infection, inflammation, trauma, etc. Cervical kyphosis after posterior decompression surgery, such as laminectomy or laminoplasty, is a common problem for spine surgeons. However, revision surgery for cervical deformity is definitely one of the most challenging areas for spine surgeons. There is no doubt that surgery for cervical deformity carries a high risk of surgery-related complications that might result in aggravation of health-related quality of life. Revision surgery is even more challenging. Hence, spine surgeons need to assess carefully the overall severity of the underlying condition before revision surgery, and try to refine the surgical strategy to secure safe surgery. Needless to say, spine surgeons are now facing great challenges in making spine surgery a much more reliable and convincing entity