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Tumor-associated macrophages (TAM), which are found in the tumor microenvironment of solid tumors, not only mediate cancer immune evasion but also promote tumor growth. The transcription factor NF-κB, which is a crucial link between inflammation and tumors, can accelerate tumor occurrence and development. NEMO, the regulatory subunit of the IKK complex, plays a pivotal role in activating the NF-κB signaling pathway. However, the function of myeloid NEMO in the tumor microenvironment remains unclear. Here, we found that conditional knockout of NEMO in myeloid cells promoted tumor growth in a transplanted cancer mouse model. In Nemofl/fl lyz-cre+/- mice, the deletion of Nemo in myeloid cells increased the recruitment of M2 macrophages and myeloid-derived suppressor cells (MDSCs) into the tumor, reduced the expression of apoptosis-related proteins, and upregulated the expression of the chemokine receptor CCR2, thereby promoting tumor growth in vivo. Then, we showed that blocking the MCP1-CCR2 pathway could inhibit tumor growth, especially in mice with myeloid NEMO deletion. In this study, we examined the mechanism of NEMO in myeloid cells and explored the role of NEMO in the prevention and treatment of cancer.
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Péptidos y Proteínas de Señalización Intracelular/genética , Células Mieloides/metabolismo , Escape del Tumor/genética , Animales , Quimiocina CCL2/genética , Quimiocina CCL2/metabolismo , Eliminación de Gen , Tolerancia Inmunológica/genética , Péptidos y Proteínas de Señalización Intracelular/metabolismo , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Células Mieloides/patología , Células Supresoras de Origen Mieloide/metabolismo , Células Supresoras de Origen Mieloide/fisiología , Neoplasias/genética , Neoplasias/inmunología , Neoplasias/metabolismo , Neoplasias/patología , Receptores CCR2/genética , Receptores CCR2/metabolismo , Transducción de Señal/genética , Células Tumorales Cultivadas , Escape del Tumor/inmunología , Microambiente Tumoral/genética , Microambiente Tumoral/inmunologíaRESUMEN
Pseudorabies virus (PRV) is an alpha herpesvirus found in many wild and domestic animals, and causes neurological diseases in humans. Several cases of PRV-induced human encephalitis accompanied with severe visual impairment have been reported. There is currently no effective treatment for severe visual impairment caused by PRV. We report a case of PRV encephalitis with severe visual impairment. The diagnosis and treatment experience of this patient is summarized to improve the awareness of clinicians. We present a 42-year-old man with PRV infection who was admitted due to intermittent fever for 5 days and unconsciousness for 1 day. He subsequently developed severe visual impairment during hospital stay. Empirical antiviral treatment with ganciclovir and sodium foscarnet was started on the day of admission and continued for > 50 days, which had significant treatment effect. Eye complications caused by PRV infection have been frequently reported in patients with PRV encephalitis. In this patient, based on the patient's condition, antiviral therapy was initiated on admission day, and according to the results of the next-generation sequencing of the cerebrospinal fluid, the duration of antiviral therapy was prolonged, which improved treatment efficacy and alleviated neurological symptoms and eye vision damage. To the best of our knowledge, this is the first report that describes partial restoration of acute vision loss associated with PRV infection after aggressive treatment. Our experience suggests that although prompt treatment cannot prevent the acute vision loss associated with PRV infection, timely anti-viral and anti-inflammatory treatment can alleviate ocular complications.
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The clinical data of 69 patients with non-HIV-related cryptococcal meningitis admitted in the Second Hospital of Hebei Medical University from January 2013 to May 2019 were analyzed retrospectively.The main presentations of 69 patients are headache,fever,nausea,vomiting, visual impairment, hearing damage.Among them, 36 cases (52%) had underlying diseases, 30 cases (43%) were misdiagnosed, and 38 cases (55%) were complicated with high intracranial pressure. Cerebrospinal fluid examination showed that leukocytes increased in 47 cases, protein increased in 55 cases, chloride decreased in 41 cases, glucose decreased in 34 cases. The imaging findings were cerebral ischemia, hydrocephalus, meningeal or cerebral parenchyma enhancement. During the induction period, 63 cases were treated with combined antifungal drugs and 6 cases were treated with single antifungal drugs. The clinical symptoms were improved in 54 cases, 9 cases were discharged automatically and 6 cases died. The clinical manifestations, routine and biochemical examination of cerebrospinal fluid, imaging findings are not specific for patients with non-HIV-related cryptococcal meningitis.So early and multiple lumbar puncture should be performed to find etiological evidence to reduce misdiagnosis. The combination of antifungal drugs during the induction period is safe and effective.
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Objective@#To explore the imaging characteristics of large vestibular aqueduct syndrome (LVAS) patients and their relationship with the acoustically evoked short latency negative response (ANSR), so as to provide reference for the diagnosis of LVAS.@*Methods@#Clinical data of 174 patients(334 ears) with LVAS diagnosed and treated by the Department of Otorhinolaryngology Head and Neck Surgery of the First Affiliated Hospital of Guangxi Medical University, from October 2009 to December 2017 were retrospectively analyzed, including 117 males and 57 females, aged from 5 months to 47 years old, with the median age of 4 years and 4 months. ABR and imaging data of patients were collected. Midpoint diameter and the outlet diameter of the vestibular aqueduct were measured on CT images, the midpoint diameter of the intraosseous parts and the extraosseous parts of enlarged endolymphatic sac(EES) were measured on MRI images. The correlation between the above measurements was analyzed by Pearson test using SPSS 17.0. According to whether ASNR was detected in ABR, the above data were divided into two groups, and the differences of the above imaging measurements were compared by the Independent-Sample Test.@*Results@#The average midpoint diameter of the vestibular aqueduct was (1.87±0.58) mm (±s, the following was the same), and the outlet diameter was (3.07±0.99) mm on CT; the average midpoint diameter of the intraosseous parts in enlarged endolymphatic sac(EES) was (2.39±1.37) mm, and the extraosseous parts was (2.50±2.18) mm on MRI. There was a correlation between the four measurements (P<0.05), among which the midpoint diameter of vestibular aqueduct was strongly positively correlated with the outlet diameter (r=0.760), and the remaining pairs were weakly correlated. ASNR was detected in 241 ears (72.16%,241/334) and undetected in 93 ears (27.84%, 93/334) of the 334 ears with LVAS. Midpoint diameter and the outlet diameter of the vestibular aqueduct in no ASNR group were smaller than the ASNR group, and the difference was statistically significant (t value was 2.814 and 2.754, P<0.05). There was no significant difference in the midpoint diameter of the intraosseous parts and the extraosseous parts of enlarged endolymphatic sac between the two groups, and the difference was no statistically significant(t value was 0.101 and 0.683, P>0.05).@*Conclusions@#There is a strong positive correlation between the midpoint diameter of vestibular aqueduct and the outlet diameter in LVAS patients. There is a certain correlation between the size of vestibular aqueduct and the size of endolymphatic sac. The smaller the diameter of vestibular aqueduct, the lower the occurrence rate of ASNR.
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Objective To investigate the relationship between rs17525495 locus polymorphism of leukotriene A4 hydrolase (LTA4H) gene and the severity of tuberculous meningitis (TBM). Methods A total of 184 TBM patients from Department of Neurology, the Second Hospital of Hebei Medical University from January 2014 to October 2016 were selected as research subjects. According to the British Medical Research Council criteria, the severity of TBM patients was divided into three stages. The single nucleotide polymorphism rs17525495 of LTA4H gene was sequenced, and the general case data, clinical manifestations and results of lumbar puncture were analyzed. Results There were 91 cases (49.5%) of CC genotypes of rs17525495 locus in LTA4H gene of 184 cases, 75 cases (40.8%) of CT genotypes and 18 cases (9.8%) of TT genotypes. The frequency of allele C was 69.8% and T was 30.2%. Patients with different genotypes were compared for their severity, clinical manifestations and lumbar puncture results. Among CC patients, the proportion of stage Ⅰ patients(54.9%, 50/91)was higher than that of stage Ⅱ(22.0%, 20/91)and Ⅲ(23.1%, 21/91). Among TT patients, the proportion of patients with stage Ⅱ(8/18)and Ⅲ(8/18)was higher than patients with stageⅠ(2/18)(χ2=15.898,P=0.003). The incidence of headache, fever, nausea and vomiting, neck stiffness, epilepsy and disturbance of consciousness was statistically analyzed. Compared with CC and CT patients, the incidence of fever(TT:13/18,CC:42/91,CT:50/75,χ2=8.932,P=0.011)and neck stiffness(TT:12/18,CC:38/91,CT:46/75,χ2=7.993,P=0.018)was higher in TT patients. Headache, nausea and vomiting, disturbance of consciousness, and the incidence of epilepsy showed no statistically significant difference. And there was no statistically significant difference in lumbar puncture pressure, chloride, protein and glucose between different genotypes. Conclusion TBM patients with mild illness frequently prompt LTA4H gene rs17525495 locus for the CC type;while patients with severe disease prompt TT type.
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Objective To investigate the features of the cerebrospinal fluid (CSF) in the modified ZeiM-Neelsen (MZN) positive tuberculous mengningitis (TBM).Methods We retrospectively reviewed the clinical data of 170 patients with tuberculous meningitis confirmed by MZN stain from December 2012 to July 2015.The purpose of the present study was to investigate the relationship of MZN staining and CSF cytology.Results Among 170 patients with TBM confirmed by MZN staining,128 cases had first detectable acid-fast bacillus (AFB) in earlier stage.The cytology included 15.5% mixed cellular cytology,58.5% lymphoid cytology,19.5% neutrophilic cytology and 6.5% normal cytology.Twenty-four cases had first detectable AFB within 1-2 months following disease onset.The cytology included 13.1% mixed cellular cytology,56.6% lymphoid cytology,21.7% neutrophilic cytology and 8.7% normal cytology.Eighteen cases had first detectable AFB 2 months after disease onset.The cytology included 26.7% mixed cellular cytology,46.7% lymphoid cytology,20.0% neutrophilic cytology,6.6% normal cytology.There was no significant difference in median time of first detectable AFB among those four types of cytology (P=0.812).There was significant difference in median time of first detectable AFB between patients with and without anti-TB therapy [21.5 (12.3,37.8) days vs.8.5 (6.0,16.3)days,P<0.001].There was no significant difference in median time MZN stain turning negative between patients with and without anti-TB therapy [11 (5.75,19.25) days vs.6(4.25,10.75)days,P=0.230].Conclusions AFB can be detectable within a month after the onset of TBM in most of cases.(MZN) positive staining is not associated with the major type of cytology.Anti-TB therapy may delay the first detectable time of AFB.
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Objective To investigate the role of S100B protein in the pathogenesis of patients with Japanese encephalitis (JE).Methods A total of 45 patients were enrolled in the Second Hospital of Hebei Medical University from August 2013 to October 2013,who were diagnosed as JE on the basis of clinical features and positive IgM antibodies against JE virus measured by enzyme-linked immunosorbent assay (ELISA) from the Center of Disease Control of Shijiazhuang.The JE patients were divided into initial phase group,acute phase group and convalescence group based on the course,mild JE group,moderate JE group and severe JE group based on the severity,MRI-no-lesion group and MRI lesions group based on the imaging findings of JE.Twelve cases with no evidence of infection in central nervous system in the meantime were chosen as control.The S100B protein was measured by ELISA.Results The content of S100B protein in cerebrospinal fluid was as follows:522.76 (393.35,620.37) pg/ml in mild JE group (acute phase group:609.77 (549.27,779.71) pg/ml,convalescence group:420.48 (344.36,453.19) pg/ml),792.09 (705.47,1 108.96) pg/ml in moderate JE group (acute phase group:770.19 (646.31,1 069.54) pg/ml,convalescence group:803.45 (602.90,1 396.84) pg/ml),and 1 021.94 (680.84,1 302.15) pg/ml in severe JE group (acute phase group:981.82 (680.84,1 826.28) pg/ml,convalescence group:989.00 (553.62,1 207.67) pg/ml).The S100B protein content was 561.52 (454.36,814.56) pg/ml,803.45 (602.90,1 104.01) pg/ml,762.22 (594.95,1 044.97) pg/ml,581.76 (442.51,1 069.10) pg/ml in MRI-no-lesion group,MRI lesions group,total acute phase group and total convalescence group,respectively.While in control group,the S100B protein content was 266.71 (205.72,390.05) pg/ml.The contents of S100B protein in moderate JE group,severe JE group,total acute phase group,total convalescence group,MRI-no-lesion group,MRI lesions group were higher than that in control group (H =4.864,5.497,5.075,3.918,2.971,4.981,P =0.000,0.000,0.000,0.000,0.009,0.000).The contents of S100B protein in mild JE group was lower than that in moderate JE group and severe JE group (H =-2.786,-3.514,P =0.032,0.003).Conclusions The level of S100B protein in cerebrospinal fluid is related with the severity,duration and imaging presentation of JE patients.The dynamic monitoring of S100B protein levels is of great significance for assessment of the patients' condition and curative effect.
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Objective To explore the diagnostic significance of Xpert MTB/RIF in cerebrospinal fluid,and evaluate the application for early diagnosis of tuberculous meningitis(TBM).Methods Sixty cases of TBM and 30 cases of non-TBM patients were selected as our subjects.Xpert MTB/RIF and modified Ziehl-Neelsen stain were performed in cerebrospinal fluid.The detection rate of the system and the resistance of the patients were analyzed.Results Eleven cases were diagnosed as the positive cases in 60 cases with TBM,and 0 case was diagnosed as TBM in control group.Sensitivity and specificity of Xpert with TBM were 18.33% and 100%,respectively.The difference of the two groups was statistically significant (P =0.014).The positive rate of definite group was 23.68%(9 cases),18.18%(2 cases) in probable group and 0% in possible group,and the difference of the three groups was statistically significant(x2 =3.070,P>0.05).The resistance rate was 36.36% (4/11).Sensitivity of the modified Ziehl-Neelsen staín was 63.33% (38/60).Eleven cases were detected positive by Xpert MTB/RIF,9 cases were positive with modified acid fast staining,and the positive rate was 18.33%,and the difference of the two methods was statistically significant (P =0.000).Conclusion Xpert MTB/RIF test is simple and rapid diagnostic method.The combination of Xpert MTB/RIF and modified ZiehlNeelsen stain will improve the efficiency of the early diagnosis of TBM.
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<p><b>OBJECTIVE</b>To evaluate the effectiveness of manual therapy and traction for lumbar disc herniation and analyze the current status of this kind of randomized clinical trial (RCT).</p><p><b>METHODS</b>Database of CNKI, VIP, WANFANG, PubMed and OVID were searched. Some relevant journals were manually retrieved. A total of 2 874 literatures on manual therapy and traction for lumbar disc herniation were collected, of which 17 articles met the inclusion criteria. The Jadad score scale was used to evaluate the quality,and RevMan5.0 was used for meta-analysis of literatures.</p><p><b>RESULTS</b>The results of the meta-analysis of all trials involved were as followed:the combined effect of the effective rate was RR = 1.10, 95% CI [1.06, 1.14], the combined effect of the cure rate was RR = 1.36, 95% CI [1.21,1.52], the combined effect of the VAS was RR = 1.37, 95% CI [1.28, 1.45], the combined effect of the JOA was RR = 4.75, 95% CI [4.40, 5.09].</p><p><b>CONCLUSION</b>The overall quality of the current RCT researches about manual therapy for lumbar disc herniation was lower,and did not support the conclusion that manual therapy was more effective than traction for lumbar disc herniation.</p>
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Humanos , Desplazamiento del Disco Intervertebral , Cirugía General , Terapéutica , Vértebras Lumbares , Cirugía General , Manipulaciones Musculoesqueléticas , Métodos , Ensayos Clínicos Controlados Aleatorios como Asunto , Tracción , MétodosRESUMEN
Objective To study the vulnerability of astrocytes bearing mutant SOD1 under the oxidative stress.Methods The cytotoxicity of the serum deprived astrocytes was measured by MTT.The level of ROS was shown by fluorescence of DCF through confocal microscopy.The expression of Nrf2,HO1 and NQO1 in the different cells was detected by Western blot.Results The level of cellular toxicity was higher in the astrocytes bearing mutant SOD1 exposed to the oxidative stress than the astrocytes hearing wild type SOD1.In the astrocytes bearing mutant SOD1,the expression of Nrf2,HO1 and NQO1 decreased.In the presence of mutant SOD1,an unexpected 44 per-cent decrease of Nrf2 was detected.This was associated with a decreases in multiple downstream phase Ⅱ detoxif-ying enzymes and antioxidant enzymes,known as NQO1 and HO1.Furthermore,our results showed that the ex-pression of NQO1 increased 1.5 and 2.5-fold by EGCG at 5 and 10 μmol/L.EGCG also elevated the expression of total Nrf2.Confocal microscopy showed that EGCG caused Nrf2 translocation from the cytoplasm to the nucleus.Conclusion Decrease in Nrf2 expression is the mechanism to explain the vulnerability of astrocytes bearing mutant SOD1 and EGCG strengthened antioxidation function by upregulating the activity of Nrf2.
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A subset of patients of amyotrophic lateral sclerosis (ALS) present with mutation of Cu/Zn superoxide dismutase 1 (SOD1), and such mutants caused an ALS-like disorder when expressed in rodents. These findings implicated SOD1 in ALS pathogenesis and made the transgenic animals a widely used ALS model. However, previous studies of these animals have focused largely on motor neuron damage. We report herein that the spinal cords of mice expressing a human SOD1 mutant (hSOD1-G93A), besides showing typical destruction of motor neurons and axons, exhibit significant damage in the sensory system, including Wallerian-like degeneration in axons of dorsal root and dorsal funiculus, and mitochondrial damage in dorsal root ganglia neurons. Thus, hSOD1-G93A mutation causes both motor and sensory neuropathies, and as such the disease developed in the transgenic mice very closely resembles human ALS.
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Animales , Humanos , Ratones , Esclerosis Amiotrófica Lateral/enzimología , Axones/patología , Modelos Animales de Enfermedad , Ganglios Espinales/patología , Ratones Transgénicos , Mitocondrias/patología , Neuronas Motoras/metabolismo , Mutación , Degeneración Nerviosa/patología , Células Receptoras Sensoriales/patología , Médula Espinal/patología , Superóxido Dismutasa/genéticaRESUMEN
Objective To investigate the effects of antioxidant response element (ARE) activator- 5,6-dihydrocyclopenta[ C ]-1,2-dithiole-3-thione (CPDT) on organotypic spinal cord cultures and to study whether this activation can protect motor neurons from oxidative stress.Methods Organotypic spinal cord cultures were prepared using lumbar spinal cord slices from 8-day-old rat.Threo-hydroxyaspartate (THA) was continuously added into the culture medium for 3 weeks,which caused selective motor neuron death. Thus,the in vitro model of amyotrophic Lateral sclerosis (ALS) was established.15,30 ?mol/L of CPDT were added into the culture medium respectively.Ventral motor neurons survival was evaluated by immunohistochemical staining with monoclonal antibody SMI-32,a nonphosphorylated neurofilament marker. Ultrastructure was observed with electronic microscope.Results The pretreatment of organotypic spinal cord cultures with different concentrations of CPDT significantly increase the total number of ventral motor neurons (15?mol/L:(15.81?6.97) perexplant;30?mol/L:(16.25?6.74) perexplant respectively) compared with THA group ((5.31?5.76) perexplant) and the former had plentiful neurite extensions (n= 15,P