Co-treatment effect of pulsed electromagnetic field (PEMF) with human dental pulp stromal cells and FK506 on the regeneration of crush injured rat sciatic nerve.

PURPOSE: The purpose of this study was to determine whether crush injured rat sciatic nerve could be benefit from pulsed electromagnetic field (PEMF) combined with human dental pulp stromal cells (hDPSCs), with FK506 (Tacrolimus) for immune suppression and neuropromotion. MATERIALS AND METHODS: Male Sprague-Dawley rats (200-250 g, 6 week old) were distributed into 6 groups (n = 18 each): control, PEMF, FK506, PEMF + hDPSCs, PEMF + FK506, and PEMF + hDPSCs + FK506 groups. hDPSCs (cell = 1 × 106/10 µl/rat) were injected at the crush site immediate after injury. FK506 was administered 3 weeks in FK506 group (0.5 mg/kg/d) while pre-op 1 d and post-op 7 d in PEMF + FK506 and PEMF + hDPSCs + FK506 group; cell tracking was done with PKH26-labeled hDPSCs (cell = 1 × 106/10 µl/rat). The rats were follow-up for 3 weeks. RESULTS: PEMF + FK506 and PEMF + hDPSCs + FK506 group showed a sharp increase in sciatic function index (SFI), axon counts, densities, and labeled neurons in dorsal root ganglia (DRG) than control at 3 weeks. Other three treatment groups also showed higher axon counts, densities, and labeled neurons than control. Higher axon counts and densities were found in PEMF + FK506 and PEMF + hDPSCs + FK506 groups comparing with PEMF group. Brain-derived neurotrophic factor (BDNF) mRNA expression pattern in nerve segment and DRG was almost same. Higher expression level in all the treatment groups was discovered in the follow-up period, but there was no significant difference. CONCLUSIONS: All treatment groups can improve regeneration of neurons following crushed injury, PEMF + FK506 and PEMF + hDPSCs + FK506 groups showed higher regeneration ability than other three groups. FK506 plays an important role during hDPSCs transplantation.

Immunopathology of and potential therapeutics for secondary hemophagocytic lymphohistiocytosis/macrophage activation syndrome: a translational perspective.

Secondary hemophagocytic lymphohistiocytosis/macrophage activation syndrome (sHLH/MAS) is a life-threatening immune disorder triggered by rheumatic disease, infections, malignancies, or medications. Characterized by the presence of hemophagocytic macrophages and a fulminant cytokine storm, sHLH/MAS leads to hyperferritinemia and multiorgan failure and rapidly progresses to death. The high mortality rate and the lack of specific treatments necessitate the development of a new drug. However, the complex and largely unknown immunopathologic mechanisms of sHLH/MAS, which involve dysfunction of various immune cells, diverse etiologies, and different clinical contexts make this effort challenging. This review introduces the terminology, diagnosis, and clinical features of sHLH/MAS. From a translational perspective, this review focuses on the immunopathological mechanisms linked to various etiologies, emphasizing potential drug targets, including key molecules and signaling pathways. We also discuss immunomodulatory biologics, existing drugs under clinical evaluation, and novel therapies in clinical trials. This systematic review aims to provide insights and highlight opportunities for the development of novel sHLH/MAS therapeutics.

SECRETED TRYPTOPHANYL-tRNA SYNTHETASE 1 IS A PROGNOSTIC MARKER IN SEPSIS PATIENTS WITHOUT MONOCYTOPENIA.

ABSTRACT: Objective: This study aimed to test whether the prognostic value of tryptophanyl-tRNA synthetase 1 (WARS1) for 28-day mortality in patients with sepsis was affected by monocytopenia. Methods: A prospective analysis of retrospectively collected samples from 74 sepsis patients was performed. WARS1, C-reactive protein (CRP), and procalcitonin were measured at admission and 24 and 72 h after admission. The prognostic value of WARS1, CRP, and procalcitonin for 28-day mortality was compared using repeated measures analysis of variance and the area under the receiver operating characteristic curve (AUROC). All analyses were performed in patients with or without monocytopenia, defined as an absolute monocyte count less than 0.1 × 10 9 cells/L. Results: WARS1 levels differed significantly between survivors and nonsurvivors when all patients and patients without monocytopenia were assessed ( P = 0.008, P < 0.001, respectively). In contrast, the WARS1 level did not differ between survivors and nonsurvivors with monocytopenia. C-reactive protein and procalcitonin levels were not different between survivors and nonsurvivors regardless of whether they had monocytopenia. The AUROCs of WARS1 at admission and 24 h for mortality were significantly higher in patients without monocytopenia (0.830, 0.818) than in patients with monocytopenia (0.232, 0.196; P < 0.001, both). When patients without monocytopenia were analyzed, the AUROCs of WARS1 for mortality were 0.830 and 0.818 at admission and 24 h, respectively, which were significantly higher than those of CRP (0.586, 0.653) and procalcitonin (0.456, 0.453) at the same time points ( P = 0.024 and 0.034, respectively). Conclusion: WARS1 is a useful biomarker for prognosis in sepsis patients without monocytopenia.

Conversion of gingerols to shogaols in ginger (Zingiber officinale roscoe) by puffing.

Effect of puffing on conversion of gingerols to shogaols, physicochemical properties as well as antioxidant and anti-inflammatory activities of puffed ginger was investigated. Puffing significantly increased extraction yield and the highest value was 12.52% at 980 kPa. The significant decrease in gingerols and increase in shogaols were occurred after puffing, respectively. Especially, 6-shogaol was dramatically increased from 4.84 to 99.10 mg/g dried ginger. Puffed ginger exhibited the higher antioxidant activities (analyzed by DPPH, ABTS, TPC, and TFC) than those of control, and they were significantly increased with increasing puffing pressure. In case of anti-inflammatory activity, puffed ginger did not inhibit NO production, but significantly inhibited TNF-α and IL-6 productions. Among gingerols and shogaols, 6-shogaol showed significantly strong correlations with both antioxidant and anti-inflammatory activities. Consequently, puffed ginger can be applied to functional food industry, which dramatically increased the contents of 6, 8, 10-shogaols, the main bioactive compounds in ginger.

Highly secreted tryptophanyl tRNA synthetase 1 as a potential theranostic target for hypercytokinemic severe sepsis.

Despite intensive clinical and scientific efforts, the mortality rate of sepsis remains high due to the lack of precise biomarkers for patient stratification and therapeutic guidance. Secreted human tryptophanyl-tRNA synthetase 1 (WARS1), an endogenous ligand for Toll-like receptor (TLR) 2 and TLR4 against infection, activates the genes that signify the hyperinflammatory sepsis phenotype. High plasma WARS1 levels stratified the early death of critically ill patients with sepsis, along with elevated levels of cytokines, chemokines, and lactate, as well as increased numbers of absolute neutrophils and monocytes, and higher Sequential Organ Failure Assessment (SOFA) scores. These symptoms were recapitulated in severely ill septic mice with hypercytokinemia. Further, injection of WARS1 into mildly septic mice worsened morbidity and mortality. We created an anti-human WARS1-neutralizing antibody that suppresses proinflammatory cytokine expression in marmosets with endotoxemia. Administration of this antibody into severe septic mice attenuated cytokine storm, organ failure, and early mortality. With antibiotics, the antibody almost completely prevented fatalities. These data imply that blood-circulating WARS1-guided anti-WARS1 therapy may provide a novel theranostic strategy for life-threatening systemic hyperinflammatory sepsis.

Effect of green tea extracts on oxaliplatin-induced peripheral neuropathy in rats.

BACKGROUND: A common side effect of oxaliplatin is peripheral neurotoxicity. Oxidative stress to dorsal root ganglion (DRG) may be one of important pathogenic mechanisms. Green tea contains four polyphenol catechins, which are known to be potent antioxidants. The present work is aimed to determine whether green tea extracts have neuroproective or palliative effects on neurotoxicity symptoms induced by oxaliplatin. METHODS: We conducted behavioral tests including sensory and thermal thresholds, an electrophysiological study, and TUNEL staining to assess neurotoxicity during the experimental period using animal models. RESULTS: A total of 14 adult rats were randomly allocated into two groups. Oxaliplatin (4 mg/kg) with or without green tea (300 mg/kg orally once daily) was administered intraperitoneally twice per week for 6 weeks. At 4 and 6 weeks after oxaliplatin administration, sensory threshold values were significantly decreased and at 6 weeks after oxaliplatin administration, thermal threshold values were significantly increased in oxaliplatin-treated rats compared with those in rat treated with oxaliplatin and green tea extracts. The electrophysiological assessment, including sensory nerve conduction and H-reflex-related sensory nerve conduction velocity, revealed no significant changes in the two groups. TUNEL staining showed no significant difference in the number of apoptotic-featured cells between the two experimental groups in the DRG or peripheral nerves, but the number of apoptotic-featured cells in DRG was higher than that in sciatic nerves within each group. CONCLUSIONS: Green tea extracts may be a useful adjuvant to alleviate sensory symptoms after oxaliplatin administration, such as allodynia, but did not prevent morphometric or electrophysiological alterations induced by oxaliplatin.

Impact of Government Intervention in Response to Coronavirus Disease 2019.

Coronavirus disease 2019 (COVID-19) led to the loss of lives and had serious social and economic effects. Countries implemented various quarantine policies to reduce the effects. The countries were divided into low- and high-risk groups based on the differences in quarantine policies and their levels of infection. Quarantine policies that significantly contributed to risk reduction were determined by analyzing 11 quarantine indicators for reducing the spread of COVID-19. The cross-tabulation and Chi-square tests were used to compare the quarantine policies by the groups. Multivariate logistic regression was used to determine the useful quarantine policies implemented by the low-risk group to verify quarantine policies for minimizing the negative effects. The analysis showed that the low- and medium-risk groups showed significant differences for 9 of the 11 indicators, and 4 of these differentiated the low- from the medium-risk group. Countries with strict quarantine policies related to workplace closure and staying at home were more likely to be included in the low-risk group. These policies had a significant impact in the low-risk countries and could contribute to reducing the spread and effects of COVID-19 in countries included in the high-risk group.

Genomically Complex Human Angiosarcoma and Canine Hemangiosarcoma Establish Convergent Angiogenic Transcriptional Programs Driven by Novel Gene Fusions.

Sporadic angiosarcomas are aggressive vascular sarcomas whose rarity and genomic complexity present significant obstacles in deciphering the pathogenic significance of individual genetic alterations. Numerous fusion genes have been identified across multiple types of cancers, but their existence and significance remain unclear in sporadic angiosarcomas. In this study, we leveraged RNA-sequencing data from 13 human angiosarcomas and 76 spontaneous canine hemangiosarcomas to identify fusion genes associated with spontaneous vascular malignancies. Ten novel protein-coding fusion genes, including TEX2-PECAM1 and ATP8A2-FLT1, were identified in seven of the 13 human tumors, with two tumors showing mutations of TP53. HRAS and NRAS mutations were found in angiosarcomas without fusions or TP53 mutations. We found 15 novel protein-coding fusion genes including MYO16-PTK2, GABRA3-FLT1, and AKT3-XPNPEP1 in 11 of the 76 canine hemangiosarcomas; these fusion genes were seen exclusively in tumors of the angiogenic molecular subtype that contained recurrent mutations in TP53, PIK3CA, PIK3R1, and NRAS. In particular, fusion genes and mutations of TP53 cooccurred in tumors with higher frequency than expected by random chance, and they enriched gene signatures predicting activation of angiogenic pathways. Comparative transcriptomic analysis of human angiosarcomas and canine hemangiosarcomas identified shared molecular signatures associated with activation of PI3K/AKT/mTOR pathways. Our data suggest that genome instability induced by TP53 mutations might create a predisposition for fusion events that may contribute to tumor progression by promoting selection and/or enhancing fitness through activation of convergent angiogenic pathways in this vascular malignancy. IMPLICATIONS: This study shows that, while drive events of malignant vasoformative tumors of humans and dogs include diverse mutations and stochastic rearrangements that create novel fusion genes, convergent transcriptional programs govern the highly conserved morphologic organization and biological behavior of these tumors in both species.

Tryptophanyl-tRNA Synthetase 1 Signals Activate TREM-1 via TLR2 and TLR4.

Tryptophanyl-tRNA synthetase 1 (WARS1) is an endogenous ligand of mammalian Toll-like receptors (TLR) 2 and TLR4. Microarray data, using mRNA from WARS1-treated human peripheral blood mononuclear cells (PBMCs), had indicated WARS1 to mainly activate innate inflammatory responses. However, exact molecular mechanism remains to be understood. The triggering receptor expressed on myeloid cells (TREM)-1 is an amplifier of pro-inflammatory processes. We found WARS1 to significantly activate TREM-1 at both mRNA and protein levels, along with its cell surface expression and secretion in macrophages. WARS1 stimulated TREM-1 production via TLR2 and TLR4, mediated by both MyD88 and TRIF, since targeted deletion of TLR4, TLR2, MyD88, and TRIF mostly abrogated TREM-1 activation. Furthermore, WARS1 promoted TREM-1 downstream phosphorylation of DAP12, Syk, and AKT. Knockdown of TREM-1 and inhibition of Syk kinase significantly suppressed the activation of inflammatory signaling loop from MyD88 and TRIF, leading to p38 MAPK, ERK, and NF-κB inactivation. Finally, MyD88, TRIF, and TREM-1 signaling pathways were shown to be cooperatively involved in WARS1-triggered massive production of IL-6, TNF-α, IFN-ß, MIP-1α, MCP-1, and CXCL2, where activation of Syk kinase was crucial. Taken together, our data provided a new insight into WARS1's strategy to amplify innate inflammatory responses via TREM-1.

Anxiolytic efficacy of repeated oral capsaicin in rats with partial aberration of oral sensory relay to brain.

OBJECTIVE: This study was conducted to examine if taste over load with oral capsaicin improves the adverse behavioural effects induced by partial aberration of oral sensory relays to brain with bilateral transections of the lingual and chorda tympani nerves. DESIGN: Male Sprague-Dawley rats received daily 1 ml of 0.02% capsaicin or water drop by drop into the oral cavity following the bilateral transections of the lingual and chorda tympani nerves. Rats were subjected to ambulatory activity, elevated plus maze and forced swim tests after 11th, 14th and 17th daily administration of capsaicin or water, respectively. The basal and stress-induced plasma corticosterone levels were examined after the end of behavioural tests. RESULTS: Ambulatory counts, distance travelled, centre zone activities and rearing were increased, and rostral grooming decreased, during the activity test in capsaicin treated rats. Behavioural scores of capsaicin rats during elevated plus maze test did not differ from control rats. Immobility during the swim test was decreased in capsaicin rats with near significance (P = 0.0547). Repeated oral capsaicin increased both the basal level and stress-induced elevation of plasma corticosterone in rats with bilateral transections of the lingual and chorda tympani nerves. DISCUSSION: It is concluded that repeated oral administration of capsaicin reduces anxiety-like behaviours in rats that received bilateral transections of the lingual and chorda tympani nerves, and that the increased corticosterone response, possibly modulating the hippocampal neural plasticity, may be implicated in the anxiolytic efficacy of oral capsaicin.

Disruption of oral sensory relay to brain increased anxiety- and depression-like behaviours in rats.

OBJECTIVE: Sensory information plays an important role to determine psycho-emotional behaviours of individuals. Lingual nerve can be damaged by dental surgery or trauma, such as physical irritation, radiation, chemotherapy, or viral infection. This study was conducted to examine the psycho-emotional effects of lingual nerve damage in which oral sensory relay to the brain is disrupted. DESIGN: Male Sprague-Dawley rats were tested for anxiety and depression-related behaviours after bilateral transections of the lingual and chorda tympani nerves (Nx) or sham operation. Tissue contents of serotonin and its metabolite in the hippocampus, hypothalamus, and nucleus accumbens were analyzed by high-performance liquid chromatography. RESULTS: Sucrose preference was reduced in Nx rats compared with sham rats, suggesting the development of anhedonia, decreased pleasure seeking behaviour, by the lingual nerves transection. Ambulatory activity was decreased, anxiety-related behaviours during the activity test increased, time spent in the open arms during elevated plus maze test decreased, and immobility duration during forced swim test increased in Nx rats compared with sham rats. Serotonin level in the hippocampus of Nx rats was decreased significantly compared with sham rats. CONCLUSIONS: Results suggest that aberration of oral sensory relay to brain may lead to the development of depression- and anxiety-related disorders, and decreased serotonergic neurotransmission in the hippocampus may play a role in its underlying mechanism.

Clinical outcome of conservative treatment of injured inferior alveolar nerve during dental implant placement.

OBJECTIVES: Infererior alveolar nerve (IAN) damage may be one of the distressing complications occurring during implant placement. Because of nature of closed injury, a large proportion is approached non-invasively. The purpose of this study was to analyze the outcomes of conservative management of the injured nerve during dental implant procedure. MATERIALS AND METHODS: Sixty-four patients of implant related IAN injury, who were managed by medication or observation from January 1997 to March 2007 at the Department of Oral and Maxillofacial Surgery, Seoul National University Dental Hospital, were retrospectively investigated. The objective tests and subjective evaluations were performed to evaluate the degree of damage and duration of sensory disturbance recovery. Tests were performed on the day of the first visit and every two months afterward. Patient's initial symptoms, proximity of the implant to the IAN, time interval between implant surgery and the first visit to our clinic, and treatment after implant surgery were analyzed to determine whether these factors affected the final outcomes. RESULTS: Among the 64 patients, 23 had a chief complaint of sensory disturbance and others with dysesthesia. The mean time until first visit to our hospital after the injury was 10.9 months.One year after nerve injury, the sensation was improved in 9 patients, whereas not improved in 38 patients, even 4 patients experienced deterioration. Better prognosis was observed in the group of patients with early visits and with implants placed or managed not too close to the IAN. CONCLUSION: Nearly 70% of patients with IAN injury during implant placement showed no improvement in sensation or dysesthesia with the conservative management. Earlier decision for active treatment needs to be considered because of possibility of deterioration of symptoms and unsatisfactory recovery.

Normal pressures and reliability of the Gaitview® system in healthy adults.

BACKGROUND: Each plantar pressure measurement system has a different accuracy and reliability, which is required to establish a range of normal values and determine the reliability. OBJECTIVES: To determine normal pressures with the Gaitview(®) system and assess its reliability. STUDY DESIGN: Single-group repeated measures. METHODS: Dynamic barefoot plantar pressure data were obtained in 30 healthy young participants. In each session, three trials were recorded by one examiner for each foot using the two-step gait initiation method, which was repeated by another examiner the same day. One week later, all of the procedures were repeated. Time-integral mean pressures were measured for each of eight anatomical foot regions. The foot contact time (CT) and the time-integral mean angle of the center of pressure (COP) were also measured. RESULTS: The greatest time-integral mean pressures were seen under the medial and lateral heel. The mean CT was 0.9 sec for both feet, and the time-integral mean angle of the COP was 9.3° for the right foot and 6.6° for the left. The intraclass correlation coefficients (ICCs) ranged from 0.69 to 0.97, and the coefficient of variation (CoV) from 9.9 to 59.97% for all parameters. CONCLUSIONS: These findings indicate that the Gaitview(®) system demonstrates good to moderate reliability. CLINICAL RELEVANCE: The Gaitview(®) AFA-50 system (alFOOTs, Seoul, Republic of Korea) has been used by clinicians in Korea, but has not been investigated in an independent study. Therefore, this study established a range of normal values and determined the reliability of the Gaitview(®) AFA-50 system.