Gorham-Stout disease(GSD)is a sporadic chronic disease characterized by progressive bone dissolution,absorption,and disappearance along with lymphatic vessel infiltration in bone-marrow cavities.Although the osteolytic mechanism of GSD has been widely studied,the cause of lymphatic hyperplasia in GSD is rarely investigated.In this study,by comparing the RNA expression profile of osteoclasts(OCs)with that of OC precursors(OCPs)by RNA sequencing,we identified a new factor,semaphorin 3A(Sema3A),which is an osteoprotective factor involved in the lymphatic expansion of GSD.Compared to OCPs,OCs enhanced the growth,migration,and tube formation of lymphatic endothelial cells(LECs),in which the expression of Sema3A is low compared to that in OCPs.In the presence of recombinant Sema3A,the growth,migration,and tube formation of LECs were inhibited,further confirming the inhibitory effect of Sema3A on LECs in vitro.Using an LEC-induced GSD mouse model,the effect of Sema3A was examined by injecting lentivirus-expressing Sema3A into the tibiae in vivo.We found that the overexpression of Sema3A in tibiae suppressed the expansion of LECs and alleviated bone loss,whereas the injection of lentivirus expressing Sema3A short hairpin RNA(shRNA)into the tibiae caused GSD-like phenotypes.Histological staining further demonstrated that OCs decreased and osteocalcin increased after Sema3A lentiviral treatment,compared with the control.Based on the above results,we propose that reduced Sema3A in OCs is one of the mechanisms contributing to the pathogeneses of GSD and that expressing Sema3A represents a new approach for the treatment of GSD.

Objective:To analyze any effect of combining hyperbaric oxygen with qingkailing on the metabolic biomarkers of consciousness disorder (CD) caused by brain trauma using metabolomics technology. Also, to screen out diagnostic markers for clinical treatment and prognosis.Methods:Thirty-six patients with a CD caused by brain trauma formed the observation group, while 40 healthy gender-, age- and ethnicity-matched individuals were the control group. Both groups were given routine supportive treatment, while the observation group additionally received hyperbaric oxygen and oral qingkailing medication. Before and after 14 days consciousness disturbance was evaluated using the Glasgow Coma Scale (GCS). Venous blood was collected for metabolomic analysis using liquid chromatography linked to a mass spectrometer to screen out specific metabolic biomarkers. Metabolic markers associated with the disease and of diagnostic significance were thus identified.Results:After the treatment the average GCS score of the observation group had improved significantly and the degree of coma was significantly relieved. Twenty-one metabolic markers were found to be significant, with creatine, proline, uric acid, acetyl-L-carnitine, histidine, proline leucine, tryptophan and 9E-octagenoic acid potentially of high diagnostic value. After the treatment, all of those markers came close to the levels observed in the healthy control group.Conclusions:Proline, leucine, 9E-octagenoleic acid, uric acid and acetyl-L-carnitine could be used for diagnosis and evaluating efficacy with such patients. Hyperbaric oxygen supplemented with qingkailing can relieve coma, correct metabolic disorders and accelerate patients′ awakening. Metabolomics provides a new method for identifying endogenous metabolic abnormalities in patients with post-traumatic consciousness disorders. It can be useful in prognosis and clinical treatment.

Maintenance of skeletal integrity requires the coordinated activity of multinucleated bone-resorbing osteoclasts and bone-forming osteoblasts. Osteoclasts form resorption lacunae on bone surfaces in response to cytokines by fusion of precursor cells. Osteoblasts are derived from mesenchymal precursors and lay down new bone in resorption lacunae during bone remodeling. Nuclear factorkappa B (NF-κB) signaling regulates osteoclast and osteoblast formation and is activated in osteoclast precursors in response to the essential osteoclastogenic cytokine, receptor activator of NF-κB ligand (RANKL), which can also control osteoblast formation through RANK-RANKL reverse signaling in osteoblast precursors. RANKL and some pro-inflammatory cytokines, including tumor necrosis factor (TNF), activate NF-κB signaling to positively regulate osteoclast formation and functions. However, these cytokines also limit osteoclast and osteoblast formation through NF-κB signaling molecules, including TNF receptor-associated factors (TRAFs). TRAF6 mediates RANKL-induced osteoclast formation through canonical NF-κB signaling. In contrast, TRAF3 limits RANKL- and TNF-induced osteoclast formation, and it restricts transforming growth factor β (TGFβ)-induced inhibition of osteoblast formation in young and adult mice. During aging, neutrophils expressing TGFβ and C-C chemokine receptor type 5 (CCR5) increase in bone marrow of mice in response to increased NF-κB-induced CC motif chemokine ligand 5 (CCL5) expression by mesenchymal progenitor cells and injection of these neutrophils into young mice decreased bone mass. TGFβ causes degradation of TRAF3, resulting in decreased glycogen synthase kinase-3β/β-catenin-mediated osteoblast formation and age-related osteoporosis in mice. The CCR5 inhibitor, maraviroc, prevented accumulation of TGFβ+/CCR5+ neutrophils in bone marrow and increased bone mass by inhibiting bone resorption and increasing bone formation in aged mice. This paper updates current understanding of how NF-κB signaling is involved in the positive and negative regulation of cytokine-mediated osteoclast and osteoblast formation and activation with a focus on the role of TRAF3 signaling, which can be targeted therapeutically to enhance bone mass.

Infectious diarrhea is an important public health problem, which has a significant impact on global disease burden. Under the background of climate change, rainstorms increase and floods occur frequently. Most studies show that the incidences of infectious diarrhea disease increase significantly after rainstorm and flood events. However, there is a lack of systematic summary on the path of rainstorm and flood events affecting the incidence of infectious diarrhea, including the key links and mechanisms underlying environmental-social interaction. This study comprehensively combed the literature from environmental factors, socio-economic and cultural factors, and population and individual susceptibility factors. The potential mechanisms of infectious diarrhea caused by rainstorm and flood events were discussed from the aspects of spreading of pathogens, affecting sanitation facilities and (or) drinking water treatment infrastructure, the regulatory role of individual and behavioral factors, and long-term effects. Based on the "pressure-state-response" model, a social driving process model of rainstorm and flood leading to incidence of infectious diarrhea was constructed. This model could provide reference for future quantitative modeling and other research directions. It is helpful to guide the public health departments to accurately identify factors affecting the incidence of infectious diarrhea after rainstorm and flood, so as to take targeted intervention measures.

Background Climate change leads to frequent heavy rainfall events, and higher incidences of bacillary dysentery after heavy rainfall have been observed. The impacts of heavy rainfall and its antecedent rainfall conditions on the disease are worth paying attention to. Objective To quantitatively analyze how the relationship between heavy rainfall events and bacillary dysentery occurrence is modified by antecedent rainfall conditions in Anhui Province and explore the different moderation effects in urban and rural contexts. Methods CN05.1 meteorological data of Anhui Province and cases of bacillary dysentery of the same area were collected from January 1, 2006 to August 31, 2017. An exposure-response Poisson regression model of heavy rainfall events and the number of daily cases was constructed to explore the moderation effect of antecedent rainfall conditions on the incidence of bacillary dysentery, and further stratified by urban and rural areas. Results This study included 129 459 cases of bacillary dysentery, with a daily average of 30.39. Compared with dry antecedent conditions without heavy rainfall, dry antecedent conditions with heavy rainfall had no obvious different effect on the incidence of bacillary dysentery for the whole province (P>0.05). But wet antecedent conditions significantly increased the risk of bacillary dysentery for the whole province after heavy rainfall (wet antecedent conditions without heavy rainfall: RR=1.281, 95%CI: 1.264-1.298; wet antecedent conditions with heavy rainfall: RR=1.267, 95%CI: 1.167-1.376). After urban and rural stratification, antecedent rainfall conditions also showed a significant moderation effect on the incidence of bacillary dysentery following heavy rainfall events. Compared with dry antecedent conditions without heavy rainfall, dry antecedent conditions with heavy rainfall had no obvious effect on the incidence of bacillary dysentery for the urban and the rural populations (P > 0.05). However, wet antecedent conditions without heavy rainfall (urban: RR=1.391, 95%CI: 1.362-1.421; rural: RR=1.222, 95%CI: 1.201-1.243) and wet antecedent conditions with heavy rainfall (urban: RR=1.364, 95%CI: 1.193-1.559; rural: RR=1.218, 95%CI: 1.098-1.352) significantly increased the risk of bacillary dysentery in both rural and urban areas. Conclusion In the influence of heavy rainfall on the incidence of bacillary dysentery in Anhui Province, antecedent rainfall conditions have a certain moderation effect in the whole province and in both urban and rural areas, and the risk of bacillary dysentery is increased under wet antecedent conditions.

Background Climate change has resulted in long-term impacts on human health. Implementing efficient adaptation strategies among primary healthcare facilities is well determined by whether staff of different genders recognize the health risks related to climate change and are willing to take active measures. Objective To investigate gender differences on perceptions of health risks and attitude towards adaptation strategies among primary healthcare workers in China, and provide relevant suggestions. Methods By adopting a multi-stage cluster sampling method, we selected 21 urban and 10 rural healthcare facilities in Guangdong Province to collect information with a questionnaire. Then chi-square test, Wilcoxon rank sum test, and logistic regression analysis were used to explore the gender differences in climate change-related health risk cognition, knowledge acquisition channels, attitudes towards adaptation strategies, main obstacles, and resource requirements among the healthcare workers. Results Of 733 participants, 38.47% (282 participants) were male and 61.53% (451 participants) were female. The percentages of male healthcare workers who agreed that climate change is happening and recognized the causes of climate change (70.21%, 60.99%) were higher than the percentages of female counterparts (59.87%, 49.00%) (both Ps＜0.05), but no obvious gender differences existed in recognizing health risks of heatwaves and infectious diseases as well as sensitive population identification (all Ps＞0.05). Most of the participants (92.50%) received climate change and health-related information from mass media like TV, radio, and newspapers. Meanwhile less men chose new media channels than women (OR=0.62, 95%CI∶ 0.41-0.94). Only 30.56% of the participants (33.69% of men and 28.60% of women) reported involvement of relevant training and lectures. Most of them (90.96%) agreed to take active measures to deal with the health threats associated with climate change without gender differences for various measures (all Ps＞0.05). The leading obstacles were hard to integrate health adaptation to climate change into main work of institutions (most female agreed, 72.28%) and the lack of funds (most male agreed, 77.66%). Increasing funding for primary health care was regarded as the most needed resource by male (86.88%) and female (89.14%). After controlling the influence of other social factors, more men agreed with the lack of funds than women (OR=1.57, 95%CI∶ 1.10-2.24). Conclusion There are some gender differences in the perceptions of health risks and adaptation strategies of climate change among primary healthcare workers: Male staff are more likely to agree with climate change and regard the lack of funds as the main obstacle, while women prefer to choose new media channels to obtain information. It’s suggested that the government and relevant institutions focus on the learning and training of climate change and health-related knowledge and expand diversified information access, and promote capacity building to cope with health threats at grass-root level, in the light of recognized gender differences among primary healthcare workers.

OBJECTIVE To establish a quantitative analysis method for the quality control components in Tenghuang jiangu capsules， and predict the possible action mechanism of the quality control components. METHODS Seven key quality control components in Tenghuang jiangu capsules were quantitatively analyzed by UHPLC-Q-Orbitrap HRMS. The “component-target” network was constructed based on network pharmacology， and the Kyoto Encyclopedia of Genes and Genomes （KEGG） pathway enrichment analysis and gene ontology （GO） function enrichment analysis were further conducted to find the key signaling pathways. RESULTS The average contents of succinic acid， hyperoside， gallic acid， kaempferol， naringin， naringenin and protocatechuic acid in 20 batches of Tenghuang jiangu capsules were 520.92， 67.67， 129.48， 4.74， 397.45， 5.66 and 376.62 μg/g， respectively. The results of network pharmacology showed that the 62 key target genes of the quality control components of the drug included AKT1， TNF， VEGFA， MMP9， PTGS2， etc. They were mainly enriched in cytokine receptor interaction， nuclear factor， tumor necrosis factor， interleukin 17， rheumatoid arthritis， Toll-like receptor and other signal pathways， involving inflammatory reaction， signal transduction， protein phosphorylation and other biological processes， kytoplasm， cell membrane and other cell components， as well as enzyme activity， energy activity and other molecular functions. CONCLUSIONS The established UHPLC- Q-Orbitrap HRMS method can be used for the quantitative analysis of the quality control components of Tenghuang jiangu capsule. Its quality control components may be mapped to inflammatory pathways related to bone diseases such as rheumatoid arthritis and Toll-like receptors through AKT1， TNF， VEGFA and other key targets， so as to play a therapeutic role.

Objective:To investigate the correlations of laminin subunit gamma 3 (LAMC3) expression with prognosis of ovarian cancer (OC).Methods:LAMC3 protein expression was measured using immunohistochemical streptavidin-peroxidase-biotin connection method (IHC). Gene expression and related clinical data in the cancer genome atlas (TCGA) cohort and clinical proteomic tumor analysis consortium (CPTAC) were applied to analyse the correlation between gene and protein expressions and clinical outcomes. Correlations between LAMC3 and clinicopathological factors were evaluated using the Pearson χ2 test (2-sided). The probability of survival and significance was calculated using the Kaplan-Meier plot. The functional clustering of biological pathways enriched from co-expressed genes of LAMC3 was used to explore the possible mechanisms that LAMC3 might contribute to poor prognosis. Results:Based on the IHC results of 216 OC tissues or ovaries (including 208 tumors and 8 normal tissues) and 51 OC tissues (including 24 chemotherapy-resistant and 27 sensitive tissues), and the protein expression data from CPTAC (including 100 primary tumors and 25 normal tissues), the results showed that the protein expression of LAMC3 was significantly decreased in OC tissues compared with normal, decreased in advanced-stage tissues compared with early-stage tissues, and decreased in drug-resistant tissues compared with sensitive tissues (all P<0.05). Furthermore, low expression of LAMC3 protein was significantly associated with poor disease-free survival (DFS) and overall survival (OS) in 51 OC tissues ( P<0.01), consistent with the results that the low levels of LAMC3 mRNA predicted short DFS and OS in 489 OC tissues of the TCGA cohort ( P<0.05). The results suggested that low expression of LAMC3 might be the adverse factors for OC development, such as drug resistance and advanced tumors, and might be a risk indicator for prognosis. Moreover, functional clustering of biological pathways enriched from the co-expressed genes of LAMC3 in TCGA ovarian cohort indicated that LAMC3 potentially involved in regulation of OC via oncogene-pathways such as Ras associated protein 1 (Rap1), mitogen-activated protein kinase (MAPK), Ras and cell adhesion-related pathways such as extra cellular matrix (ECM)-receptor interaction and focal adhesion. It indicated that LAMC3 might contribute to short survival and tumor progression by regulation of the above pathways. Conclusion:Low expression of LAMC3 is related to poor prognosis and malignant progression in OC, and thus it is expected to be a new prognostic marker and therapeutic target for clinical treatment.

Objective To investigate the changes of microstructure and blood perfusion of thalamus and basal ganglia in patients with untreated depressive disorder using diffusion kurtosis imaging (DKI) and three-dimensional arterial spin labeling (3D ASL) perfusion imaging.Methods Totally 21 untreated patients with depressive disorder (disease group) and 32 healthy volunteers (control group) underwent DKI,3D ASL and routine MR scanning were enrolled.DKI parameters (mean kurtosis [MK],axial kurtosis [Ka],radial kurtosis [Kr],fractional anisotropy [FA],mean diffusivity [MD],axial diffusivity [Da] and radial diffusivity [Dr]) and 3D ASL parameters (cerebral blood flow [CBF]) of bilateral heads of caudate nucleus,thalamus and putamens were measured and compared between the 2 groups.Results Compared with control group,Ka of left caudate head in disease group was significantly higher,while Kr was significantly lower (both P＜ 0.05).Ka of right putamens in disease group was significantly higher than that in control group (P＜0.05).Compared with control group,CBF of left caudate head and bilateral putamens decreased significantly in disease group (all P＜0.05).Conclusion Untreated depressed patients show abnormal DKI parameters and blood perfusion in basal ganglia,which indicating that microstructure integrity is impaired and blood perfusion decreases.The abnormalities in basal ganglia microstructure and blood perfusion may serve as one of the neuroimaging features of depressive disorders.

OBJECTIVE: Bipolar disorder (BD) is often misdiagnosed as unipolar depression (UD), leading to mistreatment and poor clinical outcomes. However, little is known about the similarities and differences in subcorticalgray matter regions between BD and UD. METHODS: Thirty-five BD patients, 30 UD patients and 40 healthy controls underwent diffusional kurtosis imaging (DKI) and three dimensional arterial spin labeling (3D ASL). The parameters including mean kurtosis (MK), axial kurtosis (Ka), radial kurtosis (Kr), fractional anisotropy (FA), mean diffusivity (MD), axial diffusivity (Da), radial diffusivity (Dr) and cerebral blood flow (CBF) were measured by using regions-of-interest analysis in the caudate, putamen and thalamus of the subcortical gray matter regions. RESULTS: UD exhibited differences from controls for DKI measures and CBF in the left putamen and caudate. BD showed differences from controls for DKI measures in the left caudate. Additionally, BD showed lower Ka in right putamen, higher MD in right caudate compared with UD. Receiver operating characteristic analysis revealed the Kr of left caudate had the highest predictive power for distinguishing UD from controls. CONCLUSION: The two disorders may have overlaps in microstructural abnormality in basal ganglia. The change of caudate may serve as a potential biomarker for UD.
Anisotropy ; Basal Ganglia* ; Bipolar Disorder ; Cerebrovascular Circulation ; Depressive Disorder ; Diffusion* ; Gray Matter ; Humans ; Perfusion Imaging* ; Perfusion* ; Putamen ; ROC Curve ; Thalamus*