Background::Heterotaxy (HTX) is a thoracoabdominal organ anomaly syndrome and commonly accompanied by congenital heart disease (CHD). The aim of this study was to analyze rare copy number variations (CNVs) in a HTX/CHD cohort and to examine the potential mechanisms contributing to HTX/CHD.Methods::Chromosome microarray analysis was used to identify rare CNVs in a cohort of 120 unrelated HTX/CHD patients, and available samples from parents were used to confirm the inheritance pattern. Potential candidate genes in CNVs region were prioritized via the DECIPHER database, and PNPLA4 was identified as the leading candidate gene. To validate, we generated PNPLA4-overexpressing human induced pluripotent stem cell lines as well as pnpla4-overexpressing zebrafish model, followed by a series of transcriptomic, biochemical and cellular analyses. Results::Seventeen rare CNVs were identified in 15 of the 120 HTX/CHD patients (12.5%). Xp22.31 duplication was one of the inherited CNVs identified in this HTX/CHD cohort, and PNPLA4 in the Xp22.31 was a candidate gene associated with HTX/CHD. PNPLA4 is expressed in the lateral plate mesoderm, which is known to be critical for left/right embryonic patterning as well as cardiomyocyte differentiation, and in the neural crest cell lineage. Through a series of in vivo and in vitro analyses at the molecular and cellular levels, we revealed that the biological function of PNPLA4 is importantly involved in the primary cilia formation and function via its regulation of energy metabolism and mitochondria-mediated ATP production. Conclusions::Our findings demonstrated a significant association between CNVs and HTX/CHD. Our data strongly suggested that an increased genetic dose of PNPLA4 due to Xp22.31 duplication is a disease-causing risk factor for HTX/CHD.

Objective:To prepare nanoprobes by using polydopamine (PDA) as a carrier which is modified with the sonosensitizer protoporphyrin Ⅸ (PpⅨ) and labeled with 131I, 99Tc m or 177Lu, and to explore the value of these new nanoprobes in diagnosis and combination therapy of breast cancer. Methods:PDA particles were synthesized by aqueous oxidation, and a layer of polyethylene glycol (PEG) and PpⅨ were modified on the surface to product PDA-PEG-PpⅨ. Then the nuclides 131I, 99Tc m and 177Lu were labeled on PDA, respectively, and the labeling yield and stability were determined. The cytotoxicity test was conducted by comparing the viabilities of 4T1 tumor cells in free 131I group and 131I-PDA-PEG-PpⅨ group. The 4T1 cells were divided into 7 groups according to different treatment methods: PDA-PEG-PpⅨ group, PDA-PEG-PpⅨ+ photothermal therapy (PTT) group, PDA-PEG-PpⅨ+ sonodynamic therapy (SDT) group, 131I-PDA-PEG-PpⅨ+ PTT group, 131I-PDA-PEG-PpⅨ+ SDT group, 131I-PDA-PEG-PpⅨ+ PTT+ SDT group (100 μg/ml PDA-PEG-PpⅨ, 925 kBq/ml 131I), and the control group (DMEM culture medium). The cell viabilities of those groups were compared to evaluate the therapeutic effect. 4T1 tumor bearing mouse models were established, then 99Tc m-PDA-PEG-PpⅨ was injected through the tail vein (29.6 MBq) or intratumorally (14.8 MBq) to perform gamma imaging. The independent-sample t test and one-way analysis of variance were used for data analysis. Results:The PDA particles were uniform in size, with a particle size of (160.0±1.5) nm. They had a good photothermal conversion effect. A characteristic peak consistent with PpⅨ (400 nm) appeared in the UV-Vis absorption spectrum of PDA-PEG-PpIX. In the cytotoxicity test, when the radioactivity was 1.850 or 3.700 or 7.400 MBq/ml, the cell viabilities of free 131I group and 131I-PDA-PEG-PpⅨ group were significantly different ((72.18±6.57)% vs (86.07±5.17)%, (59.31±9.06)% vs (80.85±4.21)%, (42.90±1.30)% vs (72.99±5.73)%; t values: 3.71, 4.82, 11.46, P values: 0.006, 0.001, <0.001). The 131I-PDA-PEG-PpⅨ+ PTT+ SDT combination therapy had a better killing effect on 4T1 tumor cells than the combination of 131I-PDA-PEG-PpⅨ+ PTT and 131I-PDA-PEG-PpⅨ+ SDT (cell viabilities: (10.09±2.50)% vs (16.04±2.63)%, (28.65±4.72)%; F=351.66, P<0.001). In vivo imaging showed that 99Tc m-PDA-PEG-PpⅨ was stable in mouse models and could be effectively enriched in tumors. Conclusions:A multifunctional nanoprobe based on PDA is successfully prepared. The radionuclide labeling method is simple and effective, with a good stability. 131I-PDA-PEG-PpⅨ can kill 4T1 cells efficiently. 99Tc m-PDA-PEG-PpⅨ has an obvious tumor concentration effect in mouse models.

Epigenetic modification genes are defined as genes whose products modify the epigenome directly through DNA methylation, histone modification or chromatin remodeling.More and more studies have shown that mutations in epigenetic modification genes are an important etiology of rare diseases with abnormal cardiac development.And these diseases usually affect multiple organs including heart due to the change of epigenetic components.Moreover, children′s lives and health are often threatened by a lack of effective drugs and complex cardiovascular malformations.This article reviews advances in molecule genetics of Tatton-Brown-Rahman syndrome, Kabuki syndrome, Rubinstein-Taybi syndrome, CHARGE syndrome and Sifrim-Hitz-Weiss syndrome, and mainly elaborates the mechanism of cardiovascular malformations caused by mutations in corresponding epigenetic modification genes, providing more comprehensive reference for clinical diagnosis and management.

Objective:To explore the associations between perceived built environment attributes and adults’ leisure-time physical activity in four cities of China.Methods:Multistage cluster random sampling method was used to select adults aged 25 to 64 in Hangzhou, Suzhou, Chengdu, and Qingdao. Data were collected from June 2017 to July 2018. The perception of the urban built environment was assessed by the neighborhood environment walkability scale-abbreviated (NEWS-A), and the physical activity was assessed by the International Physical Activity Questionnaire. Generalized linear mixed models were used to explore the relationship between the perceived built environment and leisure-time physical activities.Results:A total of 3 789 participants were included in the analysis. After adjusting for potential confounders, better access to public services ( OR=1.34, 95% CI: 1.02-1.75) and higher aesthetic quality ( OR=1.37, 95% CI: 1.09-1.73) were positively associated with the possibility of engaging in leisure-time physical activity in the past week. Similarly, these two attributes were positively associated with leisure-time walking. Higher scores on the perception of street connectivity were positively associated with leisure-time walking [ exp( β)=1.09, 95% CI: 1.00-1.19]. Higher residential density [ exp( β)=1.000 4, 95% CI:1.000 0-1.000 8], better access to physical activity destinations[ exp( β)=1.09, 95% CI: 1.00-1.19], and better aesthetics [ exp( β)=1.11, 95% CI:1.00-1.22] were associated with higher leisure-time physical activity. Similarly, these three attributes were positively associated with the possibility of meeting the WHO recommendations. Conclusion:Changing some urban built environment attributes may increase leisure-time physical activity.

Translational medicine means that to establish a bridge between fundamental research and clinical medicine through bidirectional translation path in order to promote the translation and application from fundamental research to clinical medicine.The purpose of traditional Chinese medicine (TCM) translational model is to collate and build one multidimensional TCM translational model,rationality carry out the research on TCM translation.Three paths have been confirmed,where are from literature research to clinical verification,from clinical application to clinical verification,and from experiment to clinical verification.In this research,methodology of one path mcntioned above could be established,which is the key technology of translational medicine.Take constipation,insomnia,and post-flu cough as target diseases to investigate the herbal compounds which could be qualified for clinical application based on preliminary work.This research not only provided clinical data to TCM translation,but also established one methodology of TCM translation path--"from experiment to clinical verification".

Objective To establish the murine models of local allergic rhinitis (LAR) and allergic rhinitis (AR) by using ovalbumin (OVA),and to investigate the relationship between them.Methods Thirty BALB/c mice were divided into 5 groups,(1) the nasally sensitized group (group A1) that was challenged with OVA by a 10 d procedure,(2) the control group of A1 that was challenged with phosphatebuffered saline (PBS),(3) the nasally sensitized group (group A2) that was challenged with OVA by a 25 d procedure,(4) the control group of A2 that was challenged with PBS,(5) the intraperitoneally sensitized group (group B).The numbers of sneezing after final challenge were counted,and the serum OVA-specific immunoglobulin E (OVA-slgE),interleukin (IL)-4,IL-13,IL-5 levels in nasal lavage fluid were measured by ELISA.Hematoxylin-eosin staining was performed to evaluate the histological change of nose and lung tissues.Graph Pad Prism 6 software was used to analyze the data.Results Nasally sensitized group A1 displayed LAR symptoms of sneezing and eosinophilic infiltrating,but without increased OVA-sIgE in serum on day 10 compared with the control group of A1(t =0.697,P ＞ 0.05),OVA-sIgE in serum of group A2(2.710 ± 1.406)ng/ml reached to statistical significance and with airway remodeling on day 25 compared with the control group of A2 ((0.221 ± 0.080) ng/ml,t =4.329,P ＜ 0.05).IL-5 and IL-13 in nasal fluid showed a significant increase in the nasally sensitized group A1,compared with the group A2 (t values were 2.442,2.804,P values were less then 0.05).Conclusions A short time intranasal instillation with OVA could establish LAR murine model,continuing OVA challenge could increase serum sIgE level and with airway remodeling.LAR mice show a unique characteristic by expressing higher IL-5 and IL-13 in nose than AR mice,but sIgE in serum remains at a normal level.

OBJECTIVETo investigate the relationship between acute graft rejection early after renal transplantation and the variations of platelet parameters.

METHODSWe retrospectively analyzed the clinical data of 167 renal transplant recipients before and within 2 months after the surgery. Before and at 1-10 days, 15 days, 30 days, 45 days and 60 days after the transplantation, 5 platelet parameters, including platelet count (PLT), platelet hematocrit (PCT), mean platelet volume (MPV), platelet volume distribution width (PDW), and large platelet ratio (P-LCR), were detected in the 35 patients with acute graft rejection within two months (AR group) and in the other 132 recipients with good graft recovery (control group).

RESULTSThe AR group and control group showed no significant difference in PLT, PCT, MPV, or P-LCR before the surgery, but the PDW was significantly higher in the AR group (t=2.18, P=0.035). These parameters were similar within 5 postoperative days between the two groups (P>0.05), but in postoperative days 6-15, the AR group showed significantly increased MPV, PDW and P-LCR compared with the control group (P<0.05). In postoperative days 6-9, MPV, PDW and P-LCR became stable in AR group but tended to decrease in the control group, showing obviously different patterns of variation between the two groups (P<0.05).

CONCLUSIONSPreoperative PDW may have a positive correlation with acute graft rejection after renal transplantation. Monitoring the variations of MPV, PDW and P-LCR may help in the diagnosis of acute graft rejection early after renal transplantation.

Blood Platelets ; cytology ; Graft Rejection ; blood ; Hematologic Tests ; Humans ; Kidney Transplantation ; Platelet Count ; Retrospective Studies

Objective To investigate the relationship between acute graft rejection early after renal transplantation and the variations of platelet parameters. Methods We retrospectively analyzed the clinical data of 167 renal transplant recipients before and within 2 months after the surgery. Before and at 1-10 days, 15 days, 30 days, 45 days and 60 days after the transplantation, 5 platelet parameters, including platelet count (PLT), platelet hematocrit (PCT), mean platelet volume (MPV), platelet volume distribution width (PDW), and large platelet ratio (P-LCR), were detected in the 35 patients with acute graft rejection within two months (AR group) and in the other 132 recipients with good graft recovery (control group). Results The AR group and control group showed no significant difference in PLT, PCT, MPV, or P-LCR before the surgery, but the PDW was significantly higher in the AR group (t=2.18, P=0.035). These parameters were similar within 5 postoperative days between the two groups (P>0.05), but in postoperative days 6-15, the AR group showed significantly increased MPV, PDW and P-LCR compared with the control group (P<0.05). In postoperative days 6-9, MPV, PDW and P-LCR became stable in AR group but tended to decrease in the control group, showing obviously different patterns of variation between the two groups (P<0.05). Conclusions Preoperative PDW may have a positive correlation with acute graft rejection after renal transplantation. Monitoring the variations of MPV, PDW and P-LCR may help in the diagnosis of acute graft rejection early after renal transplantation.

Objective To investigate the relationship between acute graft rejection early after renal transplantation and the variations of platelet parameters. Methods We retrospectively analyzed the clinical data of 167 renal transplant recipients before and within 2 months after the surgery. Before and at 1-10 days, 15 days, 30 days, 45 days and 60 days after the transplantation, 5 platelet parameters, including platelet count (PLT), platelet hematocrit (PCT), mean platelet volume (MPV), platelet volume distribution width (PDW), and large platelet ratio (P-LCR), were detected in the 35 patients with acute graft rejection within two months (AR group) and in the other 132 recipients with good graft recovery (control group). Results The AR group and control group showed no significant difference in PLT, PCT, MPV, or P-LCR before the surgery, but the PDW was significantly higher in the AR group (t=2.18, P=0.035). These parameters were similar within 5 postoperative days between the two groups (P>0.05), but in postoperative days 6-15, the AR group showed significantly increased MPV, PDW and P-LCR compared with the control group (P<0.05). In postoperative days 6-9, MPV, PDW and P-LCR became stable in AR group but tended to decrease in the control group, showing obviously different patterns of variation between the two groups (P<0.05). Conclusions Preoperative PDW may have a positive correlation with acute graft rejection after renal transplantation. Monitoring the variations of MPV, PDW and P-LCR may help in the diagnosis of acute graft rejection early after renal transplantation.

OBJECTIVETo investigate the relationship between platelet parameters and delayed graft function (DGF) early after kidney transplantation.

METHODSWe retrospectively analyzed the clinical data of 232 recipients within 2 months following kidney transplantation performed between January, 2009 and September, 2013, among whom 29 experienced DGF. The laboratory data of the preoperative and postoperative platelets were collected from all the recipients.

RESULTSCompared with the preoperative levels, the platelet number (PLT) and platelet hematocrit (PCT) were decreased on day 1 after kidney transplantation and was the lowest on day 5 (P<0.05), followed by gradual increase till reaching the highest levels on day 15 (P<0.05) and recovery of the preoperative level in days 30-60. The average platelet volume (MPV), platelet volume distribution width (PDW) and large platelet ratio (P-LCR) were increased on day 1, highest on day 7 (P<0.05), and reduced to the preoperative level on day 15, but then rose again slowly. MPV and P-LCR in days 30 to 60 and PDW in days 45 to 60 were significantly higher than the preoperative levels (P<0.05). The patients with DGF showed lowered PLT than those without DGF since day 2, and this difference was statistically significant in days 7 to 10, while PCT remained comparable between the two groups; MPV, PDW, and P-LCR were higher in DGF group than in DGF-free group with statistically significant difference on days 7, 10, and 15 (P<0.05).

CONCLUSIONPlatelet function is associated with postoperative renal graft function recovery, and platelet parameters can provide new markers for monitoring the occurrence and reversion of DGF.

Biomarkers ; Blood Platelets ; physiology ; Delayed Graft Function ; Humans ; Kidney Transplantation ; Platelet Activation ; Platelet Count ; Postoperative Period ; Retrospective Studies