Virological aspects of Epstein-Barr virus infections.

Epstein-Barr virus (EBV) is usually maintained in an asymptomatic and latent form by the host immune system, and primarily by EBV-specific cytotoxic T cells (CTLs). However, EBV has been linked to several refractory diseases such as EBV-associated hemophagocytic syndrome(EBV-AHS) and chronic active EBV infection (CAEBV). In these ectopic diseases, EBV infects T/NK cells, causing severe immunodeficiency with a very high EBV load. In recent years, the laboratory procedure to assess these types of EBV infections has been improved. In particular, real-time polymerase chain reaction (PCR) has been used to quantify the EBV load, and the MHC: peptide tetramer assay has been used to quantitate EBV-specific CTLs; these tests have been employed for the management of the illnesses associated with EBV infection. Here, we have reviewed the recent progress in the clinical application of these assays. The pathogenesis of EBV-infected T/NK cells, and the host immune response to infection, including the roles carried out by innate immunity and inflammatory cytokines, are likely to be revealed in the future.</p

Inhibitory Effects of Edaravone, a Free Radical Scavenger, on Cytokine-induced Hyperpermeability of Human Pulmonary Microvascular Endothelial Cells:A Comparison with Dexamethasone and Nitric Oxide Synthase Inhibitor

Lung hyperpermeability affects the development of acute respiratory distress syndrome (ARDS), but therapeutic strategies for the control of microvascular permeability have not been established. We examined the effects of edaravone, dexamethasone, and N-monomethyl-L-arginine (L-NMMA) on permeability changes in human pulmonary microvascular endothelial cells (PMVEC) under a hypercytokinemic state. Human PMVEC were seeded in a Boyden chamber. After monolayer confluence was achieved, the culture media were replaced respectively by culture media containing edaravone, dexamethasone, and L-NMMA. After 24-h incubation, the monolayer was stimulated with tumor necrosis factor-α (TNF-α) and interleukin-1β (IL-1β). Fluorescein-labeled dextran was added. Then the trans-human PMVEC leak was measured. Expressions of vascular endothelial-cadherin (VE-cadherin) and zonula occludens-1 protein (ZO-1) were evaluated using real-time quantitative polymerase chain reaction and immunofluorescence microscopy. The results showed that TNF-α＋IL-1β markedly increased pulmonary microvascular permeability. Pretreatment with edaravone, dexamethasone, or L-NMMA attenuated the hyperpermeability and inhibited the cytokine-induced reduction of VE-cadherin expression on immunofluorescence staining. Edaravone and dexamethasone increased the expression of ZO-1 at both the mRNA and protein levels. Edaravone and dexamethasone inhibited the permeability changes of human PMVEC, at least partly through an enhancement of VE-cadherin. Collectively, these results suggest a potential therapeutic approach for intervention in patients with ARDS

Effect of Cryotherapy after Spine Surgery

Study DesignHistorical controlled trial.PurposeTo clarify the usefulness of cryotherapy after spine surgery.Overview of LiteratureCryotherapy has generally been performed subsequent to surgery on joints and in this application its clinical effects are well understood. However, cryotherapy has yet to be used following spine surgery. Its clinical efficacy in this context is unknown.MethodsThirty six patients had undergone one level microendoscopic surgery. Sixteen were enrolled into the cooling group, with the remaining 20 making up the no postoperative cryotherapy control group. Cryotherapy was performed at 5℃ using an icing system. A silicone balloon catheter with a thermo sensor on the tip was placed in the surgical wound. The temperature in the wound was recorded every 30 minutes until the next morning. The relationship between the depth of the sensor and the temperature in the wound were investigated using simple linear regression analysis. Laboratory data, visual analogue scale (VAS) for wound pain and postoperative bleeding were investigated.ResultsThe mean temperature in the surgical wound was 37.0 in the control group and 35.0℃ in the cooling group (p<0.001). There was a positive correlation between the depth of the thermo sensor and the temperature in the wound in the cooling group (y=0.91x+30.2, r=0.67, p=0.004). There were no significant differences between the groups in terms of laboratory data, VAS or postoperative bleeding.ConclusionsThe temperature in the wound was decreased significantly by spinal surgery cryotherapy

Different interaction between HIV-1 Vif and its cellular target proteins APOBEC3G/APOBEC3F

We examined a series of site-directed point mutants of human immunodeficiency virus type 1 (HIV-1) Vif for their interaction with cellular anti-viral factors APOBEC3G/APOBEC3F. Mutant viruses that display growth-defect in H9 cells did not counteract effectively APOBEC3G and/or APOBEC3F without exception, as monitored by single-cycle infectivity assays. While growth-defective mutants of Vif C-terminal region were unable to suppress APOBEC3G/APOBEC3F, some N-terminal region mutants did neutralize one of APOBEC3G/APOBEC3F. These data have suggested that members of APOBEC3 family other than APOBEC3G/APOBEC3F are not important for anti-HIV-1 activity. Furthermore, APOPEC3G/APOBEC3F were found to differently associate with Vif in virions as analyzed by equilibrium density centrifugation. Taken together, these results indicated that interaction of HIV-1 Vif and APOBEC3G is distinct from that between Vif and APOBEC3F

Clinical Presentation of Cervical Myelopathy at C1–2 Level

Study DesignSingle-center retrospective study.PurposeTo clarify the clinical features of cervical myelopathy at the C1–2 level.Overview of LiteratureMethods for distinguishing the affected level based on myelomere symptoms or dysfunction of the conducting pathway were established. However, no symptoms have been identified as being specific to the C1–2 level segment.MethodsWe evaluated 24 patients with cervical myelopathy due to spinal cord compression at the C1–2 level. Preoperative neurological assessment were investigated and compared with the rate and site of compression of the spinal cord using computed tomography-myelography.ResultsImpaired temperature and pain sensation were confirmed in 18 of the 24 patients with that localized to the upper arms (n=3), forearm (n=9), both (n=2), and whole body (n=4). Muscle weakness was observed in 18 patients, muscle weakness extended from the biceps brachii to the abductor digiti minimi in 10 patients, and in the whole body in 8 patients. Deep tendon reflexes were normal in 10 patients, whereas hyperactive deep tendon reflexes were noted in 14 patients. The rate of spinal cord compression was significantly higher in patients with perceptual dysfunction and muscle weakness compared with those with no dysfunction. However, no significant difference in the rate and site of compression was identified in those with dysfunction.ConclusionsPerceptual dysfunction and muscle weakness localized to the upper limbs was observed in 58% and 42% of patients, respectively. Neurological abnormalities, such as perceptual dysfunction and muscle weakness, were visualized in patients with marked compression

A Feasibility Study of Postoperative Adjuvant Therapy of Carboplatin and Weekly Paclitaxel for Completely Resected Non-small Cell Lung Cancer

IntroductionRecent clinical trials have shown significant survival benefits from postoperative adjuvant therapy for respectable nonsmall cell lung cancer (NSCLC). However, evaluation of adjuvant chemotherapy with carboplatin combination is still uncertain. The purpose of the study was to test the feasibility of adjuvant chemotherapy with carboplatin and separate weekly paclitaxel after complete resection of pStage IB, II, IIIA NSCLC in a multicenter study.MethodsThe study was conducted from 2001 to 2006 in the outpatient setting. A total of 61 patients were enrolled. Patients received adjuvant chemotherapy with 4 cycles of carboplatin (AUC 5) on day 1 and paclitaxel (70 mg/m2) on day 1, 8, and 15 every 4 weeks. Primary endpoints were toxicity and chemotherapy compliance. Secondary endpoints were disease-free survival and overall survival.ResultsMore than 65% of eligible patients had pStage IIIA. The median number of chemotherapy cycles was 4 (range 1–4). Grade 3 or 4 toxicities of neutropenia were 34% (grade 4: 2%). Other hematologic adverse effects were extremely less frequent. Regarding the nonhematologic adverse effect, hair loss was frequent; however, peripheral neuralgia was less frequent. Treatment-related death was not registered. During median follow-up of 21 months, 24 patients developed recurrent disease. Estimated disease-free survival and overall survival at 2 years was 51.2% and 84.6%, respectively.ConclusionsPostoperative carboplatin and weekly paclitaxel showed favorable feasibility and acceptable toxicity in comparison with the cisplatin-containing regimen. Consequently, it is desirable that this regimen would be validated in a phase III clinical trial for NSCLC after curative resection

Comparison with Magnetic Resonance Three-Dimensional Sequence for Lumbar Nerve Root with Intervertebral Foramen

Study DesignProspective study based on magnetic resonance (MR) imaging of the lumbar spinal root of the intervertebral foramen.PurposeThis study was to compare MR three-dimensional (3D) sequences for the evaluation of the lumbar spinal root of the intervertebral foramen.Overview of LiteratureThe diagnosis of spinal disorders by MR imaging is commonly performed using two-dimensional T1- and T2-weighted images, whereas 3D MR images can be used for acquiring further detailed data using thin slices with multi-planar reconstruction.MethodsOn twenty healthy volunteers, we investigated the contrast-to-noise ratio (CNR) of the lumbar spinal root of the intervertebral foramen with a 3D balanced sequence. The sequences used were the fast imaging employing steady state acquisition and the coherent oscillatory state acquisition for the manipulation of image contrast (COSMIC). COSMIC can be used with or without fat suppression (FS). We compared these sequence to determine the optimized visualization sequence for the lumbar spinal root of the intervertebral foramen.ResultsFor the CNR between the nerve root and the peripheral tissue, these were no significant differences between the sequences at the entry of foramen. There was a significant difference and the highest CNR was seen with COSMIC-FS for the intra- and extra-foramen.ConclusionsIn this study, the findings suggest that the COSMIC-FS sequences should be used for the internal or external foramen for spinal root disorders

RGMa collapses the neuronal actin barrier against disease-implicated protein and exacerbates ALS

Repulsive guidance molecule A (RGMa) was originally identified as a neuronal growth cone–collapsing factor. Previous reports have demonstrated the multifunctional roles of RGMa mediated by neogenin1. However, the pathogenic involvement of RGMa in amyotrophic lateral sclerosis (ALS) remains unclear. Here, we demonstrated that RGMa concentration was elevated in the cerebrospinal fluid of both patients with ALS and transgenic mice overexpressing the mutant human superoxide dismutase1 (mSOD1 mice). Treatment with humanized anti-RGMa monoclonal antibody ameliorated the clinical symptoms in mSOD1 mice. Histochemical analysis revealed that the anti-RGMa antibody significantly decreased mutant SOD1 protein accumulation in the motor neurons of mSOD1 mice via inhibition of actin depolymerization. In vitro analysis revealed that the anti-RGMa antibody inhibited the cellular uptake of the mutant SOD1 protein, presumably by reinforcing the neuronal actin barrier. Collectively, these data suggest that RGMa leads to the collapse of the neuronal actin barrier and promotes aberrant protein deposition, resulting in exacerbation of the ALS pathology.Shimizu Mikito, Shiraishi Naoyuki, Tada Satoru, et al. RGMa collapses the neuronal actin barrier against disease-implicated protein and exacerbates ALS. Science Advances 9, 686 (2023); https://doi.org/10.1126/sciadv.adg3193

Open-source Software for Developing Anthropomorphic Spoken Dialog Agents

An architecture for highly-interactive human-like spoken-dialog agent is discussed in this paper. In order to easily integrate the modules of different characteristics including speech recognizer, speech synthesizer, facial-image synthesizer and dialog controller, each module is modeled as a virtual machine that has a simple common interface and is connected to each other through a broker (communication manager). The agent system under development is supported by the IPA and it will be publicly available as a software toolkit this year