Multiple sclerosis (MS) is a neuroinflammatory demyelinating disease, mediated by pathogenic T helper 17 (Th17) cells. However, the therapeutic effect is accompanied by the fluctuation of the proportion and function of Th17 cells, which prompted us to find the key regulator of Th17 differentiation in MS. Here, we demonstrated that the triggering receptor expressed on myeloid cells 2 (TREM-2), a modulator of pattern recognition receptors on innate immune cells, was highly expressed on pathogenic CD4-positive T lymphocyte (CD4⁺ T) cells in both patients with MS and experimental autoimmune encephalomyelitis (EAE) mouse models. Conditional knockout of Trem-2 in CD4⁺ T cells significantly alleviated the disease activity and reduced Th17 cell infiltration, activation, differentiation, and inflammatory cytokine production and secretion in EAE mice. Furthermore, with Trem-2 knockout in vivo experiments and in vitro inhibitor assays, the TREM-2/zeta-chain associated protein kinase 70 (ZAP70)/signal transducer and activator of transcription 3 (STAT3) signal axis was essential for Th17 activation and differentiation in EAE progression. In conclusion, TREM-2 is a key regulator of pathogenic Th17 in EAE mice, and this sheds new light on the potential of this therapeutic target for MS.
Animals ; Humans ; Mice ; CD4-Positive T-Lymphocytes/pathology* ; Cell Differentiation ; Encephalomyelitis, Autoimmune, Experimental/metabolism* ; Mice, Inbred C57BL ; Multiple Sclerosis ; Th1 Cells/pathology*

BACKGROUND:Numerous clinical studies have suggested a close relationship between obesity and osteoporosis,but whether there is a genetic causal effect between obesity and osteoporosis remains unclear. OBJECTIVE:To explore the association between obesity and osteoporosis using summary data from a large-scale genome-wide association study(GWAS)through Mendelian randomization analysis. METHODS:Obesity data were derived from summary statistics of the Genetic Investigation of Anthropometric Traits(GIANT)and the UK Biobank(UKBB).Osteoporosis data were obtained from the Genetic Factors for Osteoporosis(GeFOS)consortium,including two bone density phenotypes:total body bone mineral density(BMD)and heel BMD.The inverse variance-weighted method was the primary analysis,with the Mendelian randomization method based on Egger regression(MR-Egger)and weighted median method as supplementary approaches to calculate the causal association between genetic variations related to obesity and osteoporosis.Sensitivity analyses were conducted to validate the reliability of the results.Heterogeneity was assessed using Cochran's Q test.Horizontal pleiotropy was assessed through the MR-Egger intercept test.Leave-one-out analysis was performed to evaluate the potential influence of single nucleotide polymorphisms on the combined inverse variance-weighted estimates. RESULTS AND CONCLUSION:(1)Impact of obesity on osteoporosis:In addition to body mass index and forearm BMD,body mass index,waist-to-hip ratio,body mass index-adjusted waist-to-hip ratio,and whole-body body mass index,heel BMD,forearm BMD,lumbar spine BMD,and femoral neck BMD were causally related to each other.Further Meta-analysis revealed that obesity increased the risk of BMD(odds ratio=1.07,95%confidence interval:1.03-1.12,P<0.01).(2)Impact of osteoporosis on obesity:Apart from arm BMD and lumbar spine BMD as exposure factors showing causal relationships with obesity,other datasets indicated no causal effect between total body BMD,heel BMD,femoral neck BMD,and obesity.Additional meta-analysis demonstrated that BMD did not increase the risk of obesity(odds rate=0.99,95%confidence interval:0.98-1.01,P<0.01).There is a causal relationship between obesity and osteoporosis,suggesting that obesity may be a risk factor for osteoporosis.However,no causal association is found between osteoporosis and obesity.

Background The compound 6:2 chlorinated polyfluorinated ether sulfonic acids (6:2 Cl-PFESA) has been demonstrated abilities of strong bioaccumulation and placental barrier penetration, and it can also cross the blood-brain barrier. However, the mechanism of its neurodevelopmental toxicity in offspring induced by early-life exposure is still unknown. Objective To explore effects of 6:2 Cl-PFESA on the growth and the α-amino-3-hydroxy-5-methylisoxazole-4-propionic (AMPA) receptor gene expression in the hippocampus of offspring mice by establishing a 6:2 Cl-PFESA exposure animal model. Methods Thirty Kunming pregnant mice were randomly divided into five groups: control group, and 2, 10, 50, and 250 μg·L⁻¹ 6:2 Cl-PFESA exposure groups. The treatment groups were exposed to designed doses of 6:2 Cl-PFESA through drinking water from the first day of gestation until the end of lactation. The pups were weaned on postnatal day (PND) 21, and continued to be exposed to 6:2 Cl-PFESA through drinking water. Birth weight and body length of the offspring were recorded. Offspring mice were anesthetized and sacrificed respectively on PND7, PND21, and PND35, then their hippocampus was peeled from harvested brain tissue. The ultrastructure of hippocampus was observed via transmission electron microscopy; and the expression of AMPA receptors GluR1, GluR2, and GluR3 in the hippocampus was evaluated by real-time reverse transcription polymerase chain reaction. The learning and memory ability of the PND35 mice was measured by Morris water maze test before they were sacrificed. Results The birth weights and the lengths of the pups in the 10, 50, and 250 μg·L⁻¹ 6:2 Cl-PFESA exposure groups were (2.23±0.36), (1.92±0.20), (1.88±0.31) g, and (33.73±0.98), (32.91±1.30), (32.52±2.07) mm, respectively, which were lower than those in the control group, (2.78±0.35) g and (36.46±2.34) mm (P<0.05), respectively. The results of Morris water maze showed that the escape latencies in the orientation navigation experiment on the 4th day in the 250 μg·L⁻¹ 6:2 Cl-PFESA exposure group and on the 5th day in the 10, 50, and 250 μg·L⁻¹ 6:2 Cl-PFESA exposure groups were longer than those in the control group (P<0.05). In the space exploration experiment, the times of crossing platform in the 50 and 250 μg·L⁻¹ 6:2 Cl-PFESA exposure groups were decreased when compared with the control group (P<0.05), and the time of staying in the target quadrant of the 250 μg·L⁻¹ 6:2 Cl-PFESA exposure groups were also decreased (P<0.05). Via transmission electron microscopy, compared with the control group, the postsynaptic density was decreased and the synaptic cleft width was widened on PND35 in the 250 μg·L⁻¹ 6:2 Cl-PFESA exposure group. The mRNA expression levels of GluR1, GluR2, and GluR3 in the hippocampus of pups exposed to 250 μg·L⁻¹ 6:2 Cl-PFESA during different developmental stages were significantly lower than those in the control group (P<0.05). Except for the 2 μg·L⁻¹ 6:2 Cl-PFESA exposure group on PND7, the 6:2 Cl-PFESA exposure inhibited the mRNA expression levels of GluR1, GluR2, and GluR3 in the hippocampus of pups at different developmental stages (P<0.05). Among them, the 6:2 Cl-PFESA exposure during early development resulted in the highest decrease in the expression levels of GluR1 and GluR2 mRNA in the hippocampus of pups on PND7; GluR3 mRNA expression level in the hippocampus of the exposed pups on PND21 showed the maximum inhibitory effect; the expression levels of GluR1, GluR2, and GluR3 mRNA all showed the least decrease in the hippocampus of the exposure groups on PND35. Conclusion Early-life exposure to 6:2 Cl-PFESA may affect the growth and development of offspring mice, alter the hippocampal synaptic structure, and influence the learning and memory abilities, which may be related to their inhibitory effects on the expression levels of AMPA receptor subunits GluR1, GluR2, and GluR3 genes in the hippocampus of offspring mice at various developmental stages.

OBJECTIVE To observe the changes of static functional connectivity(sFC) and dynamic functional connectivity(dFC) of amygdala subregions in patients with bilateral idiopathic tinnitus and hearing loss(TINHL). METHODS The resting-state functional magnetic resonance imaging(fMRI) data of 30 patients with bilateral tinnitus and hearing loss and 37 normal controls(NCs) were collected to analyze the intensity changes of sFC and dFC in 8 subregions of amygdala and the whole brain in TINHL patients. RESULTS There were no significant differences in age,sex and education between the two groups. Compared with the NCs group,the sFC intensity of the right basolateral subregion and right cerebellar peduncle 1 region,the left basolateral subregion and left orbital medial frontal gyrus and left angular gyrus in TINHL group was significantly decreased. The dFC intensity of left amygdalostriatal subregion and left precuneus in TINHL group was increased,but the dFC intensity was reduced in the left basolateral subregion and right angular gyrus as well as between the right superficial subregion and right medial orbital of superior frontal gyrus. CONCLUSION Among the 8 subregions of amygdala,the bilateral basolateral subregions,the left amygdalostriatal subregion and the right superficial region shown abnormal functional connectivity with other regions of the brain,which are the important parts of emotional abnormalities in TINHL.

OBJECTIVE To analyze the clinical characteristics of pulsatile tinnitus induced by sigmoid sinus abnormalities in high and normal intracranial pressure states.METHODS There were 66 patients of pulsatile tinnitus induced by sigmoid sinus abnormalities,including 55 cases of sigmoid sinus wall dehiscence and 11 cases of sigmoid sinus diverticulum.The index of transverse sinus stenosis(ITSS)was used to assess intracranial pressure in magnetic resonance venography(MRV).We obtained 41 cases in intracranial hypertension group and 25 cases in normal intracranial pressure group.The age,gender,handedness,tinnitus lateralization,mean arterial pressure(MAP),body mass index(BMI),tinnitus duration,tinnitus frequency,tinnitus loudness,tinnitus handicap inventory(THI)and blood biochemical examination were recorded to analyze.RESULTS The BMI was 24.98 kg/m2(22.87 kg/m2,28.46 kg/m2)and 24.01 kg/m2(20.34 kg/m2,25.03 kg/m2)and THI score was 45.59±23.47 and 33.84±20.13 in intracranial hypertension group and normal intracranial pressure group,respectively.Compared with normal intracranial pressure group,the BMI and THI of intracranial hypertension group were significantly increased(P was 0.047 and 0.042 respectively).No significant difference were found in other indicators.CONCLUSION There are some different characteristics in pulsatile tinnitus induced by sigmoid sinus abnormalities in high and normal intracranial pressure states,which manifest obviously increased BMI and THI score in pulsatile tinnitus patients with intracranial hypertension.

Copy number variations (CNVs), which can affect the role of long non-coding RNAs (lncRNAs), are important genetic changes seen in some malignant tumors. We analyzed lncRNAs with CNV to explore the relationship between lncRNAs and prognosis in bladder cancer (BLCA). Messenger RNA (mRNA) expression levels, DNA methylation, and DNA copy number data of 408 BLCA patients were subjected to integrative bioinformatics analysis. Cluster analysis was performed to obtain different subtypes and differently expressed lncRNAs and coding genes. Weighted gene co-expression network analysis (WGCNA) was performed to identify the co-expression gene and lncRNA modules. CNV-associated lncRNA data and their influence on cancer prognosis were assessed with Kaplan-Meier survival curve. Multi-omics integration analysis revealed five prognostic lncRNAs with CNV, namely

Objective:To explore the diagnostic value of Caprini score for acute pulmonary embolism(APE).Methods:Totally 2 764 patients with suspected APE admitted to Yuncheng Central Hospital were enrolled from January 2012 to January 2019, and 312 patients were diagnosed APE and assigned to APE group finally.Among the patients without APE, 312 patients(control group) were matched with the patients in APE group according to age, gender, weight, blood pressure, surgical history, etc.The general clinical data of the two groups were collected, and the Caprini score of each patient was recorded.The differences between the two groups in clinical data and Caprini score were compared.The area under curves(AUC) of receiver operating characteristic(ROC) was calculated to predict the diagnostic efficacy of Caprini scale for patients with APE.Results:The Caprini score of the APE group was significantly higher than that of the control group[(5.41±2.47)points vs.(2.16±1.28)points, t=1.180, P=0.004]. The Caprini score had a favorable diagnostic efficacy for patients with suspected APE(AUC=0.915, 95% CI: 0.878-0.995, P<0.001), and when the 3.5 cutoff value of Caprini score was determined, the specificity and sensitivity were 87.76% and 95.24%, respectively, with 7.778 of positive likelihood ratio, 0.054 of negative likelihood ratio, and 0.83 of Youden index. Conclusion:Caprini score has strong diagnostic efficacy in patients with APE.

Objective To explore the differences in autophagic expression levels between hypertrophic scar (HS) tissue and normal skin tissue,and further investigate the relationship between hypertrophic scar formation and autophagy protein expression through the rabbit ear hypertrophic scar model.Methods 30 patients with hypertrophic scar were collected.One hypertrophic scar tissue and one normal skin tissue were harvested.The relative expressions of LC3,P62 and Beclin-1 in each tissue specimen were detected by immunohistochemistry and Western blot.Western blot was used to detect the autophagic-associated protein LC3 (MAPLC3),P62 and Beclin-1 in the hypertrophic scar tissue of rabbit ear and the corresponding normal tissue of rabbit ears at 4 weeks,8 weeks,12 weeks,and 24 weeks,and further explore their clinical significance.Results In vivo,the expression of hypertrophic scar tissue protein LC3 and Beclin-1 was significantly stronger than that in normal skin tissue (P ＜ 0.05).The expression of P62 was significantly weaker than that in normal skin tissue (P ＜ 0.05).In animal experiments,during the process of HS formation,the protein expression of LC3 gradually increased,while the protein expression of P62 gradually decreased;the protein expression of Beclin-1 was higher than that of normal rabbit ears tissue,with statistically significant differences (P ＜ 0.05).Conclusions The expression of LC3 and Beclin-1 in human hypertrophic scar tissues is higher than that in normal tissues.While the expression of P62 is lower than that in normal tissues.That is,the expression of autophagy in human hypertrophic scar tissue showed an upward trend in a certain period of time,and was significantly higher than that in normal tissue.

Objective To observe any short-term analgesic effect of using heat stimulation at acupoints for treating migraine headaches without aura.Methods Totally 120 migraine patients were randomly divided into an observation group and a control group,each of 60.Both groups was given 5mg of Sibelium orally each night for 4 weeks.The observation group additionally received heat and pain stimulation at the Feng Chi,Shuai Gu,Yang Ling Quan,Wai Guan,Tai Yang and Yin Tang acupoints.The heat was in 0.3 s pulses at 54.5° with an inter-pulse interval of 10 s.Each acupuncture point was stimulated 5 times in rotation for a total of 20 min daily for 4 weeks.The frequency of headache attacks,their duration,their intensity rated using a visual analogue scale (VAS),accompanying symptoms and responses to a migraine-specific quality of life questionnaire (MSQ) were recorded before and after the treatment.Results After the treatment there was significantly greater improvement in the observation group compared to the control group in terms of headache frequency,headache duration,VAS ratings,and accompanying symptoms.The observation group also improved significantly more in terms of the average limitation dysfunction score,dysfunction score and emotion score on the MSQ.Moreover,the total effectiveness rate of the observation group (95.0％) was significantly higher than that of the control group (80.0％).During the treatment,no adverse reactions were found in terms of heart rate or blood pressure,and no abnormal manifestations such as infection,redness or swelling were observed at the stimulation sites.Conclusion Heat and pain stimulation at acupoints has a significant short-term analgesic effect on migraine without aura.Such treatment is safe and reliable,with few side effects.It provides a new treatment method for migraine patients and is worthy of clinical promotion and application.

Objective To investigate procalcitonin (PCT) and C reactive protein (CRP) expression in patients with puerperal infection after cesarean section and its clinical significance.Methods From January 2014 to January 2016,134 cases of cesarean section puerperal infection patients in our hospital were enrolled in observation group,according to 1∶3 matching,we selected 402 cases of cesarean section without puerperal infection as the control group.Then the levels of PCT and CRP in two groups were detected.Results CRP and PCT levels of 24 h,48 h and 72 h of the patients in the observation group were (13.16 ± 1.06)mg/L and (1.05 ±0.42)g/L,(15.15 ± 1.50)mg/L and (1.67 ±0.31)g/L,(16.01 ± 2.32) mg/L and (2.10 ± 0.92) g/L respectively,significantly higher than the control group (P ＜ 0.05);72 h CRP and PCT levels of pelvic cavity peritonitis patients were (17.13 ± 1.46)mg/L and (2.81 ± 0.97) g/L respectively,significantly higher than that in patients with vulvovaginal and cervicitis,endometritis and fallopian tube (P ＜ 0.05);72 h CRP and PCT in patients with endometritis and fallopian tube inflammation were (15.89 ± 1.06) mg/L and (2.06 ± 0.83) g/L,significantly higher than that of vaginal and Cervicitis Patients (P ＜ 0.05).Conclusions CRP and PCT increase rapidly in patients with puerperal infection after cesarean section,and there are a certain relationship with puerperal infection disease and they are of certain clinical application value.