Causal effects of body mass index, education, and lifestyle behaviors on intervertebral disc disorders: Mendelian randomization study.

This study aimed to investigate the causal risk factors for intervertebral disc disorders (IVDD) to help establish prevention strategies for IVDD-related diseases. We performed two-sample Mendelian randomization analyses to investigate the causal effects of body mass index (BMI), education, and lifestyle behaviors (sedentary behavior, smoking, and sleeping) on thoracic/thoracolumbar/lumbosacral IVDD (TTL-IVDD) and cervical IVDD. The inverse-variance weighted (IVW) method was conducted as the primary model to pool effect sizes using odds ratio and 95% confidence interval. The strength of causal evidence was evaluated from the effect size and different Mendelian randomization methods (MR-Egger/weighted median/weighted mode method, Cochran's Q test, leave-one-out analysis, MR Steiger, MR-PRESSO and radial IVW analyses). We found strong evidence for the causal associations between IVDD and BMI (TTL-IVDD, 1.27 [1.18, 1.37], p = 2.40 × 10-10 ; cervical IVDD, 1.24 [1.12, 1.37, p = 6.58 × 10-5 ), educational attainment (TTL-IVDD, 0.57 [0.51, 0.64], p = 9.64 × 10-21 ; cervical IVDD, 0.58 [0.49, 0.68], p = 1.78 × 10-10 ), leisure television watching (TTL-IVDD, 1.54 [1.29, 1.84], p = 7.80 × 10-6 ; cervical IVDD, 1.65 [1.29, 2.11], p = 0.0001), smoking initiation (TTL-IVDD, 1.37 [1.25, 1.50], p = 1.78 × 10-10 ; cervical IVDD, 1.32 [1.16, 1.51], p = 6.49 × 10-5 ), short sleep (TTL-IVDD, 1.28 [1.09, 1.49], p = 0.0027; cervical IVDD, 1.53 [1.21, 1.94], p = 0.0008), or frequent insomnia (TTL-IVDD, 1.20 [1.11, 1.30], p = 1.54 × 10-5 ; cervical IVDD, 1.37 [1.20, 1.57], p = 7.80 × 10-6 ). This study provided genetic evidence that increased BMI, low educational attainment, sedentary behavior by leisure television watching, smoking initiation, short sleep, and frequent insomnia were causal risk factors for IVDD. More efforts should be directed toward increasing public awareness of these modifiable risk factors and mobilizing individuals to adopt healthy lifestyles.

YY1 transcription factor induces proliferation and aerobic glycolysis of neuroblastoma cells via LDHA regulation.

The present study investigated the effect of transcription factor yin yang 1 (YY1) on aerobic glycolysis and cell proliferation in neuroblastoma and its mechanism. Neuroblastoma cell lines were used to investigate the association between YY1 and lactate dehydrogenase A (LDHA) expression. Cell Counting Kit (CCK)-8 and clone formation experiments were used to detect the cell viability. The interaction of YY1 and LDHA was detected using chromatin immunoprecipitation assay. Glucose uptake, intra/extracellular lactate and pyruvate and LDHA expression were evaluated using standard methods. Reverse transcription quantitative PCR, western blotting and gene overexpression or silencing were undertaken to explore the biological effects and underlying mechanisms of transcriptional regulators in NB cells. The results demonstrated that YY1 was significantly upregulated in neuroblastoma cell lines. The results of aerobic glycolysis and CCK-8 indicated that YY1 significantly promoted the proliferation and aerobic glycolysis of neuroblastoma cells. In addition, chromatin immunoprecipitation-PCR results demonstrated that YY1 was directly bound to the promoter LDHA. Overexpression of LDHA could reverse the inhibitory effect of sh-YY1 on aerobic glycolysis and proliferation of neuroblastoma cells. In conclusion, YY1 could induce aerobic glycolysis and proliferation of neuroblastoma cell lines, and may directly mediate the regulation of LDHA. These findings may provide novel insight for the treatment of neuroblastoma.

Detection of erosions and fat metaplasia of the sacroiliac joints in patients with suspected sacroiliitis using a chemical shift-encoded sequence (IDEAL-IQ).

PURPOSE: To evaluate the performance of a chemical shift-encoded sequence called IDEAL-IQ for detecting sacroiliac joint (SIJ) erosions and fat metaplasia compared to T1-weighted fast spin echo (T1 FSE) using qualitative and quantitative analysis. METHOD: Thirty-four patients with suspicion of sacroiliitis who underwent both MRI and CT were included. Each SIJ was divided into four quadrants for analysis. For qualitative analysis, the diagnostic performance of IDEAL-IQ and T1 FSE for erosions were compared by the McNemar test, using CT as the gold standard. Cochran's Q and McNemar tests were used to determine differences in structural changes detected by different imaging methods. For quantitative analysis, two-sample t test and receiver operating characteristic (ROC) analysis were used for the analysis of histogram parameters of proton density fat fraction (PDFF). RESULTS: Diagnostic sensitivity and accuracy of IDEAL-IQ were greater than T1 FSE for erosions (all P < 0.05). IDEAL-IQ and CT detected more erosions than T1 FSE (all P < 0.05). IDEAL-IQ did not statistically significantly differ from T1 FSE for the detection of fat metaplasia (P = 0.678). All histogram parameters were different between groups with and without fat metaplasia (all P < 0.05) and could distinguish the two groups (all P < 0.05). PDFF75th was the most effective histogram parameter. CONCLUSION: IDEAL-IQ detects SIJ erosions with better accuracy than T1 FSE and is similar to T1 FSE for detection of fat metaplasia, enabling further quantitative analysis of the latter via histogram analysis.

Themis is indispensable for IL-2 and IL-15 signaling in T cells.

To perform their antiviral and antitumor functions, T cells must integrate signals both from the T cell receptor (TCR), which instruct the cell to remain quiescent or become activated, and from cytokines that guide cellular proliferation and differentiation. In mature CD8+ T cells, Themis has been implicated in integrating TCR and cytokine signals. We investigated whether Themis plays a direct role in cytokine signaling in mature T cells. Themis was required for IL-2- and IL-15-driven CD8+ T cell proliferation both in mice and in vitro. Mechanistically, we found that Themis promoted the activation of the transcription factor Stat and mechanistic target of rapamycin signaling downstream of cytokine receptors. Metabolomics and stable isotope tracing analyses revealed that Themis deficiency reduced glycolysis and serine and nucleotide biosynthesis, demonstrating a receptor-proximal requirement for Themis in triggering the metabolic changes that enable T cell proliferation. The cellular, metabolic, and biochemical defects caused by Themis deficiency were corrected in mice lacking both Themis and the phosphatase Shp1, suggesting that Themis mediates IL-2 and IL-15 receptor-proximal signaling by restraining the activity of Shp1. Together, these results not only shed light on the mechanisms of cytokine signaling but also provide new clues on manipulating T cells for clinical applications.

Multi-Source Coupling Based Analysis of the Acoustic Radiation Characteristics of the Wheel-Rail Region of High-Speed Railways.

Based on elastic mechanics, the fluid-structure coupling theory and the finite element method, a high-speed railway wheel-rail rolling-aerodynamic noise model is established to realize the combined simulation and prediction of the vibrations, rolling noise and aerodynamic noise in wheel-rail systems. The field test data of the Beijing-Shenyang line are considered to verify the model reliability. In addition, the directivity of each sound source at different frequencies is analyzed. Based on this analysis, noise reduction measures are proposed. At a low frequency of 300 Hz, the wheel-rail area mainly contributes to the aerodynamic noise, and as the frequency increases, the wheel-rail rolling noise becomes dominant. When the frequency is less than 1000 Hz, the radiated noise fluctuates around the cylindrical surface, and the directivity of the sound is ambiguous. When the frequency is in the middle- and high-frequency bands, exceeding 1000 Hz, both the rolling and total noise exhibit a notable directivity in the directions of 20-30° and 70-90°, and thus, noise reduction measures can be implemented in these directions.

PD-1 and BTLA regulate T cell signaling differentially and only partially through SHP1 and SHP2.

Blockade antibodies of the immunoinhibitory receptor PD-1 can stimulate the anti-tumor activity of T cells, but clinical benefit is limited to a fraction of patients. Evidence suggests that BTLA, a receptor structurally related to PD-1, may contribute to resistance to PD-1 targeted therapy, but how BTLA and PD-1 differ in their mechanisms is debated. Here, we compared the abilities of BTLA and PD-1 to recruit effector molecules and to regulate T cell signaling. While PD-1 selectively recruited SHP2 over the stronger phosphatase SHP1, BTLA preferentially recruited SHP1 to more efficiently suppress T cell signaling. Contrary to the dominant view that PD-1 and BTLA signal exclusively through SHP1/2, we found that in SHP1/2 double-deficient primary T cells, PD-1 and BTLA still potently inhibited cell proliferation and cytokine production, albeit more transiently than in wild type T cells. Thus, PD-1 and BTLA can suppress T cell signaling through a mechanism independent of both SHP1 and SHP2.

Histogram analysis with computed tomography angiography for discriminating soft tissue sarcoma from benign soft tissue tumor.

To investigate the feasibility of histogram analysis with computed tomography angiography (CTA) in distinguishing between soft tissue sarcomas and benign soft tissue tumors. Fourty nine patients (23 men, mean age = 44.3 years, age range = 25-64) with pathologically-confirmed soft tissue sarcoma (n = 24) or benign soft tissue tumors (n = 25) in the lower extremities undergoing CTA for tumor evaluation were retrospectively analyzed. Two radiologists separately performed histogram analyses of CT density with CTA images by drawing a region of interest (ROI). The 10th (P10), 25th (P25), 50th (P50), 75th (P75), 90th percentiles (P90), mean, and standard deviations (SD) of measured tumor density were obtained along with measurements of the absolute value of kurtosis (AVK), absolute value of skewness (AVS), and inhomogeneity for each tumor. Intra-class correlation coefficients (ICC) were calculated to determine inter- and intra-reader variability in parameter measurements. The Mann-Whitney U test was used to compare histogram parameters between soft tissue sarcomas and benign soft tissue tumors. Receiver operator characteristic (ROC) curves were constructed to evaluate the accuracy of tumor discrimination. ICC was greater than 0.7 for AVS, AVK, and inhomogeneity, and >0.9 for mean, SD, and all percentile measures. There was no significant difference in P10, P25, P50, P75, P90, mean, or SD between soft tissue sarcomas and benign tumors (P > .05). AVS, AVK, and inhomogeneity were significantly higher in soft tissue sarcomas (P < .05). Areas under the curve (AUC) were 0.81, 0.83, and 0.84 for AVS, AVK, and inhomogeneity respectively. AUC were below 0.6 for mean, SD, and all percentiles.Skewness, kurtosis, and inhomogeneity measurements derived from histogram analysis from CTA distinguish between soft tissue sarcomas and benign soft tissue tumors.

Intravoxel incoherent motion diffusion MR and diffusion kurtosis imaging for discriminating atypical bone metastasis from benign bone lesion.

OBJECTIVES: To investigate the feasibility of intravoxel incoherent motion (IVIM) diffusion MR and diffusion kurtosis imaging (DKI) in discriminating atypical bone metastasis from benign bone lesion in patients with tumors. METHODS: Patients with bone lesions in lower extremity suspected of metastases were enrolled in this prospective study. IVIM diffusion MR and DKI were performed before biopsy. Apparent diffusion coefficient (ADC), true diffusion (D), perfusion fraction (f) and perfusion-related pseudodiffusion (D*) were generated with IVIM, while mean kurtosis (MK) and mean diffusion (MD) generated with DKI. Two radiologists blinded to pathology results separately measured these parameters for each lesion through drawing region of interest. Intraclass correlation coefficient was used to determine the inter-reader viability in measurement. The patients with pathology-confirmed metastasis or benign lesion were analyzed. The Mann-Whitney test was used to compare IVIM and DKI parameters between metastasis group and benign lesion group. Receiver operating characteristic curves were constructed to evaluate the ability of discrimination. RESULTS: Bone lesions from 28 patients (metastasis, n = 15; benign lesion, n = 13; mean age = 55 years; age range, 34~77) were analyzed with IVIM and DKI. Intraclass correlation coefficient was greater than 0.8 for all parameters. ADC, D and MD were significantly lower in metastases versus benign lesions (p <0.05). MK and f value were significantly higher in metastases versus benign lesions (p<0.05). D* was not significantly different between the two groups (p>0.05). Areas under curve for ADC, D, f, MK and MD were 0.935, 0.939, 0.891, 0.840 and 0.844 respectively. CONCLUSIONS: IVIM and DKI derived parameters distinguish between atypical bone metastasis and benign bone lesion in selected patients with tumors. ADVANCES IN KNOWLEDGE: Bone metastasis and benign bone lesion differ in water molecular diffusion. Intravoxel incoherent motion derived true diffusion distinguishes between atypical bone metastasis and benign lesion.

Memory-Related Synaptic Plasticity Is Sexually Dimorphic in Rodent Hippocampus.

Men are generally superior to women in remembering spatial relationships, whereas the reverse holds for semantic information, but the neurobiological bases for these differences are not understood. Here we describe striking sexual dimorphism in synaptic mechanisms of memory encoding in hippocampal field CA1, a region critical for spatial learning. Studies of acute hippocampal slices from adult rats and mice show that for excitatory Schaffer-commissural projections, the memory-related long-term potentiation (LTP) effect depends upon endogenous estrogen and membrane estrogen receptor α (ERα) in females but not in males; there was no evident involvement of nuclear ERα in females, or of ERß or GPER1 (G-protein-coupled estrogen receptor 1) in either sex. Quantitative immunofluorescence showed that stimulation-induced activation of two LTP-related kinases (Src, ERK1/2), and of postsynaptic TrkB, required ERα in females only, and that postsynaptic ERα levels are higher in females than in males. Several downstream signaling events involved in LTP were comparable between the sexes. In contrast to endogenous estrogen effects, infused estradiol facilitated LTP and synaptic signaling in females via both ERα and ERß. The estrogen dependence of LTP in females was associated with a higher threshold for both inducing potentiation and acquiring spatial information. These results indicate that the observed sexual dimorphism in hippocampal LTP reflects differences in synaptic kinase activation, including both a weaker association with NMDA receptors and a greater ERα-mediated kinase activation in response to locally produced estrogen in females. We propose that male/female differences in mechanisms and threshold for field CA1 LTP contribute to differences in encoding specific types of memories.SIGNIFICANCE STATEMENT There is good evidence for male/female differences in memory-related cognitive function, but the neurobiological basis for this sexual dimorphism is not understood. Here we describe sex differences in synaptic function in a brain area that is critical for learning spatial cues. Our results show that female rodents have higher synaptic levels of estrogen receptor α (ERα) and, in contrast to males, require membrane ERα for the activation of signaling kinases that support long-term potentiation (LTP), a form of synaptic plasticity thought to underlie learning. The additional requirement of estrogen signaling in females resulted in a higher threshold for both LTP and hippocampal field CA1-dependent spatial learning. These results describe a synaptic basis for sexual dimorphism in encoding spatial information.

Estrogen's Effects on Excitatory Synaptic Transmission Entail Integrin and TrkB Transactivation and Depend Upon ß1-integrin function.

Estradiol (E2) perfusion rapidly increases the strength of fast excitatory transmission and facilitates long-term potentiation in the hippocampus, two effects likely related to its memory-enhancing properties. Past studies showed that E2's facilitation of transmission involves activation of RhoA signaling leading to actin polymerization in dendritic spines. Here we report that brief exposure of adult male hippocampal slices to 1 nM E2 increases the percentage of postsynaptic densities associated with high levels of immunoreactivity for activated forms of the BDNF receptor TrkB and ß1-integrins, two synaptic receptors that engage actin regulatory RhoA signaling. The effects of E2 on baseline synaptic responses were unaffected by pretreatment with the TrkB-Fc scavenger for extracellular BDNF or TrkB antagonism, but were eliminated by neutralizing antisera for ß1-integrins. E2 effects on synaptic responses were also absent in conditional ß1-integrin knockouts, and with inhibition of matrix metalloproteinases, extracellular enzymes that generate integrin ligands. We propose that E2, acting through estrogen receptor-ß, transactivates synaptic TrkB and ß1-integrin, and via mechanisms dependent on integrin activation and signaling, reversibly reorganizes the spine cytoskeleton and thereby enhances synaptic responses in adult hippocampus.

Comparison of adenosine stress and dobutamine stress by real-time myocardial contrast echocardiography in detecting myocardium ischemia in dogs.

BACKGROUND: Real-time perfusion imaging (RTPI) using ultrasound contrast agents has shown good "accuracy" in detecting myocardial infarction, however its accuracy in the assessment of peri-infarct ischemia and stress echocardiography are not known. The aim of this study was to determine the accuracy of RTPI in assessment of peri-infarct ischemia during dobutamine and adenosine stress. METHODS: We employed the RTPI modality (Agilent and ATL Philips) in a canine model (18 dogs) of distal coronary occlusion and proximal coronary stenosis. Using coronary flow probe recordings, the physiologic significance of proximal coronary stenosis was established by confirming abolition of the coronary reserve. The contrast agent Optison was given as a slow bolus injection at baseline, during prolonged distal coronary occlusion, during adenosine bolus stress and during dobutamine stress. Triphenyltetrazolium chloride (TTC) staining was used to verify a distal infarction. RTPI recordings at baseline, the distal coronary occlusion and stress protocols were randomly mixed and reviewed blindly. RESULTS: In all but one dog, RTPI detected a distal infarct as small as 9% of the left ventricle. The sensitivity, specificity and overall diagnostic accuracy of RTPI in the detection of distal infarcts were: 94%, 89% and 92%, respectively. The sensitivity, specificity, and overall diagnostic accuracy of RTPI in the assessment of peri-infarction ischemia were 83%, 92% and 88% for adenosine stress and 95%, 86% and 91% for dobutamine stress, respectively. CONCLUSIONS: Even small distal infarcts can be detected by RTPI; peri-infarct ischemia can be accurately recognized by RTPI during stress; adenosine and dobutamine stress appear equally reliable in the RTPI evaluation of peri-infarct ischemia.