Targeting the PRC2-dependent epigenetic program alleviates urinary tract infections.

Urinary tract infection (UTI) is a pervasive health problem worldwide. Patients with a history of UTIs suffer increased risk of recurrent infections, a major risk of antibiotic resistance. Here, we show that bladder infections induce expression of Ezh2 in bladder urothelial cells. Ezh2 is the methyltransferase of polycomb repressor complex 2 (PRC2)-a potent epigenetic regulator. Urothelium-specific inactivation of PRC2 results in reduced urine bacterial burden, muted inflammatory response, and decreased activity of the NF-κB signaling pathway. PRC2 inactivation also facilitates proper regeneration after urothelial damage from UTIs, by attenuating basal cell hyperplasia and increasing urothelial differentiation. In addition, treatment with Ezh2-specific small-molecule inhibitors improves outcomes of the chronic and severe bladder infections in mice. These findings collectively suggest that the PRC2-dependent epigenetic reprograming controls the amplitude of inflammation and severity of UTIs and that Ezh2 inhibitors may be a viable non-antibiotic strategy to manage chronic and severe UTIs.

Diagnosis of hepatocellular carcinoma using a novel anti-glycocholic acid monoclonal antibody-based method.

Glycocholic acid (GCA) is a novel identified biomarker for hepatocellular carcinoma (HCC). However, clinical pathological study of GCA has not been extensive due to the limited availability of anti-GCA monoclonal antibodies (mAbs) and restricted detection methods. In the present study, using human GCA conjugated with bovine serum albumin as the immunogen to immunize BALB/c mice, a novel anti-GCA mAb was generated and characterized. The isotypes of heavy chain and light chain of anti-GCA mAb were examined to be IgG2a and κ, respectively, with a high affinity constant (2.6×108 mol/l). The anti-GCA mAb binds GCA with high specificity and sensitivity, and the 50% inhibitory rate was 77.09 ng/ml. The present study also established a rapid, sensitive and efficient indirect competitive ELISA analysis using this anti-GCA mAb to detect the level of GCA produced by different HCC cell lines. Therefore, the present study may successfully develop a novel method for early HCC diagnosis, and also provide insights for further research and treatment of HCC.

Application of sedation-agitation scale in conscious sedation before bronchoscopy in children.

This retrospective study investigated the application of the sedation-agitation scale (SAS) in pediatric bronchoscopy by observing its effects on sedative dosages and adverse reactions.Children who underwent sedation before bronchoscopy, during the period from January 2014 to June 2017, were divided into control and SAS groups. Patients in the control group were administered a single dose of 0.1 to 0.3 mg/kg midazolam, based on physicians' clinical experience. The initial dose of midazolam in the SAS group was 0.1 mg/kg, and was adjusted based on the SAS score, as evaluated by physicians. Between-group comparisons were made of midazolam dose; adverse reactions of midazolam, such as agitation, delirium, excessive sedation, and respiratory depression; operating time of bronchoscopy; and number of participants.No statistically significant differences in gender, age distribution, weight, or disease composition were observed between the groups. The midazolam dose, operating time, and number of participants at different ages were all lower in the SAS group than in the control group. Fewer adverse drug reactions, such as intraoperative agitation and delirium, were noted in the SAS group. Moreover, the overall number of participants was reduced, and the overall operating time was less than that in the control group.Application of SAS for assessment of sedation during pediatric bronchoscopy can guide individualized administration of midazolam, reduce midazolam dose while achieving an ideal sedative effect, reduce adverse reactions, and improve operator experience. Hence, its use should be promoted for pediatric patients undergoing bronchoscopy under local anesthesia and conscious sedation.

Low molecular weight heparin may benefit nephrotic remission in steroid­sensitive nephrotic syndrome via inhibiting elastase.

Low molecular weight heparin (LMWH) has a structure similar to heparan sulfate, which exerts anti­inflammatory effects via inhibiting elastase (Ela) activity. Release of Ela along the glomerular capillary wall may induce glomerular injury and proteinuria. The present study aimed to investigate the influence of LMWH on steroid­sensitive nephrotic syndrome (SSNS) and the potential underlying mechanism. A total of 40 SSNS patients and 20 healthy controls were recruited. SSNS patients were treated with LMWH and prednisone simultaneously (LMWH+pred group) or with prednisone alone (pred group). Proteinuria, urinary glycosaminoglycans (GAGs), serum Ela and urinary creatinine levels were measured. The nephrotic period of SSNS was 15.93±5.78 days. The nephrotic period of SSNS in LMWH+pred group was significantly reduced compared with the pred group (14.13±4.56 vs. 18.63±6.49 days; P<0.05). At the follow­up of the SSNS patients, there was no statistically significant difference in number of relapses between the LMWH+pred and pred groups. Proteinuria (2.51±0.97 g/24 h), urinary GAG levels (4.92±0.87 mg/mmol creatinine) and serum Ela levels (77.64±10.99 ng/l) were significantly greater in the nephrotic period of SSNS compared with the remission period (0.107±0.026 g/24 h, 1.53±0.27 mg/mmol Cr and 41.92±7.81 ng/l, respectively) and the healthy control group (0.098±0.027 g/24 h, 1.40±0.26 mg/mmol creatinine and 38.43±9.83 ng/l, respectively; P<0.05). During the remission period, urinary GAG and serum Ela levels in the LMWH+pred group were significantly reduced compared with the pred group (P<0.05), whereas proteinuria did not differ between these groups (P>0.05). Positive correlations were revealed between urinary GAG excretion and proteinuria (r=0.877; P<0.05), proteinuria and serum Ela levels (r=0.844; P<0.05) and serum Ela levels and urinary GAG excretion (r=0.881; P<0.05). The results of the present study indicated that elevated serum Ela levels may induce proteinuria by degrading GAGs in the glomerular basement membrane in children with SSNS. LMWH may benefit nephrotic remission of SSNS via inhibiting Ela.

Placement of tunneled cuffed vascular catheter through superior vena cava puncture.

OBJECTIVE: The purpose of this study was to assess the feasibility and safety of placement of tunneled cuffed catheters through direct percutaneous puncture of the superior vena cava (SVC) in patients with occluded right and left innominate veins. METHODS: This was a retrospective review of all patients with right and left innominate vein occlusions who underwent tunneled catheter placement with direct SVC puncture between January 2012 and December 2014. Under fluoroscopic guidance with the patient in a supine position, a 5F catheter was placed at the distal end of the SVC through the femoral vein, iliac vein, or hepatic vein. This catheter was used as a fluoroscopic target for the puncture. Following the guidance of fluoroscopy, the puncture needle and sheath were placed through a transcutaneous route with the insertion site 0.5 to 1.0 cm lateral-inferior to the clavicle head of the sternocleidomastoid, with the pathway inferior (caudal) to the clavicle, which allowed access of the guidewire and placement of a tunneled central venous catheter. RESULTS: The procedure succeeded in all 16 patients. During follow-up (mean, 12 months; range, 3-36 months), access failure due to thrombosis was observed in one patient. The remaining continued to function well until the end of the follow-up period or until the death of the patient (n = 3). No pneumothorax occurred. The most common complication was mediastinal hematoma after puncture failure in five patients. The diameter of the maximum hematoma was 2.2 cm, and all resolved spontaneously. CONCLUSIONS: In patients with central vein occlusion and exhaustion of conventional insertion sites, a tunneled central venous catheter can be safely placed through SVC puncture by the transcutaneous route.

High expression of special AT-rich sequence binding protein-1 predicts esophageal squamous cell carcinoma relapse and poor prognosis.

Previous studies of the roles of special AT-rich sequence binding protein-1 (SATB1) in the development and progression of cancer have suggested that SATB1 promotes cancer cell metastasis. The aim of the present study is to evaluate the role of SATB1 in the progression and prognosis of esophageal squamous cell carcinoma (ESCC). ESCC tissues were collected from 102 patients and SATB1 mRNA expression was measured by reverse transcription-quantitative polymerase chain reaction. The association between expression of SATB1 mRNA with clinicopathological features and prognosis was assessed, and the prognosis of ESCC was evaluated using Kaplan-Meier survival curves. In the 102 ESCC tissues, SATB1 mRNA expression correlated with the clinical tumor node metastasis stage (P<0.05), but not with any other clinicopathological features (including age, gender, tumor differentiation grade, adjuvant radio/chemotherapy, or the consumption of alcohol and use of cigarettes) (P>0.05). The disease-free survival (DFS) and overall survival (OS) of patients with high SATB1 expression was decreased compared with those with low SATB1 expression. The present study indicated that SATB1 mRNA expression was associated with the postoperative recurrent and poor prognosis in ESCC. SATB1 may be a novel marker for predicting the recurrent and worse prognosis of ESCC.

Respiratory Syncytial Virus Aggravates Renal Injury through Cytokines and Direct Renal Injury.

The purpose of this study was to investigate the relationship between renal injury and reinfection that is caused by respiratory syncytial virus (RSV) and to analyze the mechanism of renal injury. Rats were repeatedly infected with RSV on days 4, 8, 14, and 28, then sacrificed and examined on day 56 after the primary infection. Renal injury was examined by transmission electron microscopy and histopathology. The F protein of RSV was detected in the renal tissue by indirect immunofluorescence. Proteinuria and urinary glycosaminoglycans (GAGs), serum levels of albumin, urea nitrogen, and creatinine, secretion of cytokines, T lymphocyte population and subsets, and dendritic cell (DC) activation state were examined. The results showed that renal injury was more serious in the reinfection group than in the primary infection group. At a higher infection dose, 6 × 106 PFU, the renal injury was more severe, accompanied by higher levels of proteinuria and urinary GAGs excretion, and lower levels of serum albumin. Podocyte foot effacement was more extensive, and hyperplasia of mesangial cells and proliferation of mesangial matrix were observed. The maturation state of DCs was specific, compared with the primary infection. There was also a decrease in the ratio of CD4+ to CD8+ T lymphocytes, due to an increase in the percentage of CD8+ T lymphocytes and a decrease in the percentage of CD4+ T lymphocytes, and a dramatic increase in the levels of IL-6 and IL-17. In terms of the different reinfection times, the day 14 reinfection group yielded the most serious renal injury and the most significant change in immune function. RSV F protein was still expressed in the glomeruli 56 days after RSV infection. Altogether, these results reveal that RSV infection could aggravate renal injury, which might be due to direct renal injury caused by RSV and the inflammatory lesions caused by the anti-virus response induced by RSV.

Expression Depression of CD300LG-γ in Human Pulmonary Carcinoma.

The expression of CD300LG-γ at mRNA and protein level was detected by semiquantitative reverse transcription-polymerase chain reaction (PCR), quantitative real-time PCR, and western blot, and compared by t-test analysis. The results of semiquantitative reverse transcription-PCR showed that the mRNA expression of CD300LG-γ was significantly lower in pulmonary carcinoma tissues, compared to tumor-adjacent tissues. The results of quantitative real-time PCR confirmed this finding. The mRNA level of CD300LG-γ in pulmonary carcinoma tissues compared with tumor-adjacent tissues was 0.436-fold in a median. The results of western blot indicated that CD300LG-γ protein was expressed in both pulmonary carcinoma and tumor-adjacent tissues, and the expression level was significantly lower in pulmonary carcinoma tissues compared with tumor-adjacent tissues. Both mRNA and protein levels of CD300LG-γ in pulmonary carcinoma tissues were significantly lower than that in tumor-adjacent tissues, which might lead to inhibition of killing function of immunocytes, resulting in immune escape of lung cancer cells.

New insight into the pathogenesis of minimal change nephrotic syndrome: Role of the persistence of respiratory tract virus in immune disorders.

The pathogenesis of minimal change nephrotic syndrome (MCNS) is a complex clinical problem which, unfortunately, has been in need of significant breakthroughs for decades. Improved understanding of the mechanisms is important to develop effective treatment strategies. To our knowledge, the pathogenesis of MCNS is multifactorial, involving both intrinsic and extrinsic factors, reasonable to be regarded as a "long chain" cascade reaction. Current studies implicating that the disease could probably be caused by immune disorders, however, have focused merely on the middle or terminal of this "long chain". It remains unclear what really triggers the immune disorders. It is noteworthy that the close association of respiratory tract infection with the occurrence, relapse and aggravation of nephrotic syndrome has been confirmed for over two decades. Derived from what we demonstrated in earlier studies, that the persistence of respiratory tract virus may contribute to the onset and development of MCNS, this review summarizes current evidence investigating the possible mechanisms of viral persistence, and discusses the role of viral persistence in the pathogenesis of MCNS. The key point is: whether the persistence of respiratory tract virus results in immune disorders. The available evidence under review also highlight the fact that the background of genetic susceptibility to the disease was found in many patients, which could be triggered by extrinsic factors, e.g. by the infection of respiratory tract virus.

Effects of hemoperfusion in the treatment of childhood Henoch-Schönlein purpura nephritis.

PURPOSE: Immune mediators play a role in the pathogenesis of Henoch-Schönlein purpura (HSP) nephritis. Since hemoperfusion (HP) is able to eliminate the immune mediators in many diseases, we investigated the effects of HP in the treatment of HSP nephritis. METHODS: 90 children with HSP nephritis were enrolled and followed up for 12 months. They were assigned to the HP group or the control group, respectively. Both groups were treated with corticosteroids and other supportive therapy. Patients in the HP group received HP for 3 consecutive days. The major outcomes included the percentage of patients with HSP nephritis, extrarenal symptoms, and recurrences and changes in serum levels of immune mediators. RESULTS: The percentage of patients with nephritis in the HP group was less than that in the control group at each visit; the differences for prortions at 1, 3, 6, 12 months were 16.7% (p = 0.133), 31.3% (p = 0.004), 10.8% (p = 0.283), and 20.6% (p = 0.003), respectively. The severity and duration of abdominal and joint pains in the acute phase were significantly improved in the HP group compared to those in the control group. Hemoperfusion also significantly reduced patients' serum levels of immune mediators including IgA, TNF-α, IL-6, and LTB4. However, recurrences between the two groups were not significantly different. CONCLUSIONS: Hemoperfusion in combination with corticosteroid was more effective than corticosteroid alone in treating HSP nephritis. The effects may be achieved by eliminating immune mediators.

Ability of low-molecular-weight heparin to alleviate proteinuria by inhibiting respiratory syncytial virus infection.

AIM: Low-molecular-weight heparin (LMWH) is a negatively charged glycoprotein and has a very similar structure to that of cell surface heparin sulfate (HS). Thus, LMWH, an analog of HS, may inhibit positively charged respiratory syncytial virus (RSV) infection through cooperative electrostatic association. METHODS: In this study, rats were respectively treated with 400 IU/kg LMWH before, during or after being inoculated with 6 x 10(6) plaque-forming unit (PFU) RSV. RSV and normal control groups were respectively inoculated by RSV and virus-free Dulbecco's modified Eagle's medium (DMEM). HeLa cells in vitro were pretreated with LMWH, elastase (ELA), heparinase (HpaIII) and protamine before being inoculated with 6 x 10(1) PFU RSV. RSV infectivity was determined by in situ hybridization and plaque assay. RESULTS: After inoculation, the urinary protein excretion and serum parameters in LMWH-treated rats were significantly lower than those in the RSV group. No abnormalities of glomerular structure were observed in LMWH-treated groups whereas swelling and slight hypercellularity in minority glomeruli and foot process effacement were observed in the RSV group. RSV RNA of LMWH-treated rats had weaker expression than that of the RSV group. In vitro, RSV infection in RSV + LMWH, HpaIII + ELAI, protamine + ELAI, ELAI, HpaIII and protamine treatment cells were significantly lower than that of the RSV control, and that in RSV + LMWH was the least. There were no significant differences in RSV infection between ELAI + LMWH and RSV control. CONCLUSION: Our study confirmed that there is a correlation between RSV and proteinuria in rats. LMWH can alleviate proteinuria in rats through inhibiting RSV from binding with HS which plays an important role in the onset of RSV infection.