Bilobetin induces kidney injury by influencing cGMP-mediated AQP-2 trafficking and podocyte cell cycle arrest.

BACKGROUND: Ginkgo biloba (Gb) extracts have been used as a traditional Chinese medicine. Gb contains flavonoids, which are considered to be its active ingredients and have been used in the treatment of a variety of diseases. However, few scientific research studies on the side effects of flavonoid in Gb have been reported. PURPOSE: The present study aimed to investigate the effect of bilobetin on the kidney of Sprague-Dawley (SD) rats. STUDY DESIGN AND RESULT: In this study, rats were injected with 50 mg/kg of bilobetin, a biflavone isolated from Gb, for 7 days and aristolochic acid was used as positive controls. The results showed that the body weight and urine output of the rats were dramatically decreased, and urinary protein increased after the intraperitoneal injection of bilobetin compared with the control group. Bilobetin treatment showed vacuolar degeneration in the renal tubular epithelium, glomerular atrophy by histostaining, and podocyte fusion by electron microscopy. This study further showed that bilobetin promoted the trafficking of aquaporin 2 (AQP-2) onto the plasma membrane to achieve the function of urine concentration by in vivo study in rats and in vitro study in IMCD-3 cells. The redistribution of AQP-2 is due to increased expression of cGMP in IMCD-3 cells, which in turn promoted the phosphorylation of AQP-2 at site Ser-256. The proteinuria caused by bilobetin may be attributed to podocyte cell cycle arrest at G2/M transition, which is may associated with AKT and MAPK signaling. CONCLUSIONS: The current study showed that bilobetin has some side effects on kidneys at a dose of 50 mg/kg in SD rats and provides insight into the potential detrimental effects of monomeric ingredients in Gb.

Potential hepatic and renal toxicity induced by the biflavonoids from Ginkgo biloba.

Evidence continues to grow on potential health risks associated with Ginkgo biloba and its constituents. While biflavonoid is a subclass of the flavonoid family in Ginkgo biloba with a plenty of pharmacological properties, the potential toxicological effects of biflavonoids remains largely unknown. Thus, the aim of this study was to investigate the in vitro and in vivo toxicological effects of the biflavonoids from Ginkgo biloba (i.e., amentoflavone, sciadopitysin, ginkgetin, isoginkgetin, and bilobetin). In the in vitro cytotoxicity test, the five biflavonoids all reduced cell viability in a dose-dependent manner in human renal tubular epithelial cells (HK-2) and human normal hepatocytes (L-02), indicating they might have potential liver and kidney toxicity. In the in vivo experiments, after intragastrical administration of these biflavonoids at 20 mg·kg-1·d-1 for 7 days, serum biochemical analysis and histopathological examinations were performed. The activity of alkaline phosphatase was significantly increased after all the biflavonoid administrations and widespread hydropic degeneration of hepatocytes was observed in ginkgetin or bilobetin-treated mice. Moreover, the five biflavonoids all induced acute kidney injury in treated mice and the main pathological lesions were confirmed to the tubule, glomeruli, and interstitium injuries. As the in vitro and in vivo results suggested that these biflavonoids may be more toxic to the kidney than the liver, we further detected the mechanism of biflavonoids-induced nephrotoxicity. The increased TUNEL-positive cells were detected in kidney tissues of biflavonoids-treated mice, accompanied by elevated expression of proapoptotic protein BAX and unchanged levels of antiapoptotic protein BCL-2, indicating apoptosis was involved in biflavonoids-induced nephrotoxicity. Taken together, our results suggested that the five biflavonoids from Ginkgo biloba may have potential hepatic and renal toxicity and more attentions should be paid to ensure Ginkgo biloba preparations safety.

Outcomes of Surgical Management of Neurogenic Thoracic Outlet Syndrome: A Systematic Review and Bayesian Perspective.

PURPOSE: To provide a summary of the relevant evidence on outcomes of transaxillary first rib excision (TAFRE), supraclavicular first rib excision with scalenectomy (SCFRE), and supraclavicular release leaving the first rib intact (SCR) for patients with neurogenic thoracic outlet syndrome (TOS), and interpret the treatment effects from a Bayesian perspective. METHODS: A systematic literature search and review were performed. Random-effects meta-analyses were conducted to estimate success rate and complete relief rate of each procedure. The probabilities of specified success rates and complete relief rates were calculated using a Bayesian method. Sensitivity analyses for TOS type, neck trauma, and cervical rib were performed. Complications of each procedure were also reviewed. RESULTS: Data were extracted from 17 studies of TAFRE, 9 of SCFRE, and 14 of SCR to conduct the meta-analyses. The pooled success rate and complete relief rate were 0.76 (95% confidence interval [95% CI)], 0.65-0.85) and 0.53 (95% CI, 0.38-0.68) for TAFRE, 0.77 (95% CI, 0.68-0.85) and 0.57 (95% CI, 0.41-0.72) for SCFRE, and 0.85 (95% CI, 0.76-0.92) and 0.61 (95% CI, 0.35-0.84) for SCR, respectively. The probabilities of success rate greater than 70% were 90%, 87%, and 99% for TAFRE, SCFRE, and SCR, respectively. If the success rate of 80% or greater was considered, the probabilities were 34%, 31%, and 91%, respectively. The probabilities of complete relief rate of 50% or greater were 67%, 71%, and 69% for TAFRE, SCFRE, and SCR, respectively. Sensitivity analyses showed similar results. The complication rates for TAFRE, SCFRE, and SCR were, respectively, 22.5%, 25.9%, and 12.6%. CONCLUSIONS: The SCR has a high probability of success rate greater than 80%; both TAFRE and SCFRE have high probabilities of a success rate greater than 70% but only low probabilities of success rate greater than 80%. The TAFRE and SCFRE have more complications than SCR. TYPE OF STUDY/LEVEL OF EVIDENCE: Therapeutic IV.

Low serum gastrin associated with ER+ breast cancer development via inactivation of CCKBR/ERK/P65 signaling.

BACKGROUND: Gastrin is an important gastrointestinal hormone produced primarily by G-cells in the antrum of the stomach. It normally regulates gastric acid secretion and is implicated in a number of human disease states, but how its function affects breast cancer (BC) development is not documented. The current study investigated the suppressive effects of gastrin on BC and its underlying mechanisms. METHODS: Serum levels of gastrin were measured by enzyme-linked immunosorbent assay (ELISA) and correlation between gastrin level and development of BC was analyzed by chi-square test. Inhibitory effects of gastrin on BC were investigated by CCK-8 assay and nude mice models. Expressions of CCKBR/ERK/P65 in BC patients were determined through immunohistochemistry (IHC) and Western blot. Survival analysis was performed using the log-rank test. RESULTS: The results indicated that the serum level of gastrin in BC patients was lower compared with normal control. Cellular and molecular experiments indicated that reduction of gastrin is associated with inactivation of cholecystokinin B receptor (CCKBR)/ERK/P65 signaling in BC cells which is corresponding to molecular type of estrogen receptor (ER) positive BC. Furthermore, we found that low expression of gastrin/CCKBR/ERK /P65 was correlated to worse prognosis in BC patients. Gastrin or ERK/P65 activators inhibited ER+ BC through CCKBR-mediated activation of ERK/P65. Moreover, combination treatment with gastrin and tamoxifen more efficiently inhibited ER+ BC than tamoxifen alone. CONCLUSIONS: We concluded that low serum gastrin is related to increased risk of ER+ BC development. The results also established that CCKBR/ERK/P65 signaling function is generally tumor suppressive in ER+ BC, indicating therapies should focus on restoring, not inhibiting, CCKBR/ERK/P65 pathway activity.

Cost-Effectiveness of Diagnostic Strategies for Suspected Scaphoid Fractures.

OBJECTIVES: The aim of this study was to assess the cost effectiveness of multiple competing diagnostic strategies for suspected scaphoid fractures. METHODS: With published data, the authors created a decision-tree model simulating the diagnosis of suspected scaphoid fractures. Clinical outcomes, costs, and cost effectiveness of immediate computed tomography (CT), day 3 magnetic resonance imaging (MRI), day 3 bone scan, week 2 radiographs alone, week 2 radiographs-CT, week 2 radiographs-MRI, week 2 radiographs-bone scan, and immediate MRI were evaluated. The primary clinical outcome was the detection of scaphoid fractures. The authors adopted societal perspective, including both the costs of healthcare and the cost of lost productivity. The incremental cost-effectiveness ratio (ICER), which expresses the incremental cost per incremental scaphoid fracture detected using a strategy, was calculated to compare these diagnostic strategies. Base case analysis, 1-way sensitivity analyses, and "worst case scenario" and "best case scenario" sensitivity analyses were performed. RESULTS: In the base case, the average cost per scaphoid fracture detected with immediate CT was $2553. The ICER of immediate MRI and day 3 MRI compared with immediate CT was $7483 and $32,000 per scaphoid fracture detected, respectively. The ICER of week 2 radiographs-MRI was around $170,000. Day 3 bone scan, week 2 radiographs alone, week 2 radiographs-CT, and week 2 radiographs-bone scan strategy were dominated or extendedly dominated by MRI strategies. The results were generally robust in multiple sensitivity analyses. CONCLUSIONS: Immediate CT and MRI were the most cost-effective strategies for diagnosing suspected scaphoid fractures. LEVEL OF EVIDENCE: Economic and Decision Analyses Level II. See Instructions for Authors for a complete description of levels of evidence.

Exact multisoliton solutions of general nonlinear Schrödinger equation with derivative.

Multisoliton solutions are derived for a general nonlinear Schrödinger equation with derivative by using Hirota's approach. The dynamics of one-soliton solution and two-soliton interactions are also illustrated. The considered equation can reduce to nonlinear Schrödinger equation with derivative as well as the solutions.

Functions and mechanisms of intermittent negative pressure for osteogenesis in human bone marrow mesenchymal stem cells.

The present study aimed to determine the mechanism by which low­intensity intermittent negative pressure affects the differentiation and proliferation of human mesenchymal stem cells (MSCs). Alkaline phosphatase (ALP) activity, type I collagen and vascular endothelial growth factor (VEGF) were detected to analyze differentiation. MTT and flow cytometry were employed to measure proliferation and apoptosis. Western blot analysis was used to examine endoplasmic reticulum (ER) stress­associated factors. This study was divided into two groups, including a normal group (without any treatment) and vacuum group (treated with a vacuum). There was a significant decrease in the proliferation of cells in the vacuum group. The number of cells in S phase was reduced significantly, while the rate of apoptosis and the activity of ALP were markedly increased under vacuum conditions. Expression of collagen type I and VEGF was significantly increased, and the ratio of osteoprotegrin to osteoprotegrin ligand was decreased significantly in the vacuum group. ER stress­associated proteins, p­PRKR­like ER kinase, inositol­requiring enzyme 1 and cleaved activating transcription factor 6, as well as the downstream factors, were activated when treated with negative pressure. In conclusion, treatment with low­intensity and intermittent negative pressure may inhibit the proliferation of MSCs and trigger ER stress­associated cellular apoptosis, further enhancing osteogenesis activity and inducing differentiation to osteoblasts.

CDH1 promoter polymorphism and stomach cancer susceptibility.

The relationship of stomach cancer susceptibility and the presence of E-cadherin (CDH1) promoter -160 C/A polymorphism had been reported with conflicting results. To further explore the association of this polymorphism with stomach cancer susceptibility, we performed an extensive search of relevant studies and carried out a meta-analysis to obtain a more precise estimate. A total of 16 studies including 2,611 cases and 3,788 controls were involved in this meta-analysis. When all studies involved, the meta-analysis results suggest no statistically significant association between CDH1 -160 C/A polymorphism and stomach cancer risk (CA vs. CC: OR = 1.01, 95% CI: 0.85-1.19; AA vs. CC: OR = 1.05, 95% CI: 0.75-1.46; dominant model: OR = 1.02, 95% CI: 0.86-1.20; recessive model: OR = 1.04, 95% CI: 0.76-1.41). When subgroup analyses were performed by ethnicity, the A-allele carriers conferred a decreased stomach cancer risk in Asians (AA vs. CC: OR = 0.67, 95% CI: 0.47-0.96; dominant model: OR = 0.85, 95% CI: 0.72-0.99), but no statistically significant association was found in Caucasians. In conclusion, this meta-analysis suggests that CDH1 -160 A-allele may play a protective role of stomach cancer development in Asians but not in Caucasians.

[The clinical value of cartilaginous surface and corresponding osseous contour of patellofemoral joint].

OBJECTIVE: to investigate if the cartilaginous surface and corresponding osseous contour of the patellofemoral joint match in the axial plane for providing theoretical basis with evaluating alignment of patellofemoral joint and designing the part of patellofemoral joint in knee prosthesis. METHODS: from January 2009 to March 2010, 9 human cadaver knees were prepared, which chandra of patellofemoral joint didn't degenerate. Each specimen was sectioned in the axial plane at 20° to 30° knee flax. The cross-sections revealed characteristics in the bony anatomy and corresponding articular surface geometry of the patellofemoral joint in the axial plane. Evaluating parameters included osseous patella congruence angle (OPCA), chondral patella congruence angle (CPCA), patella chondral convex point parameter (PCCPP), patella subchondral osseous convex point parameter (PSOCPP), the parameters of the deepest (chondral or osseous) point of the intercondylar sulcus. After that, the osseous and cartilaginous contours and subchondral osseous contours of the patella in the axial plane were analyzed through MRI data of 11 patients who didn't degenerate in patellofemoral joint cartilage. Parameters as same as cadaver knees were compared. RESULTS: data from specimens of OPCA was (-4.5 ± 1.1)°, CPCA was (0.5 ± 0.8)°, PCCPP was 1.13 ± 0.11, PSOCPP was 1.67 ± 0.14, PCDPIS was 1.35 ± 0.28, PODPIS was 1.38 ± 0.33. Date from MRI of OPCA was (-3.8 ± 1.4)°, CPCA was (0.7 ± 1.0)°, PCCPP was 1.05 ± 0.21, PSOCPP was 1.73 ± 0.18, PCDPIS was 1.41 ± 0.21, PODPIS was 1.37 ± 0.27. The patella exhibited significant differences in the bony vs. chondral anatomy (P < 0.05), but the intercondylar sulcus nearly match in the bony vs. chondral anatomy. CONCLUSIONS: the cartilaginous surface and corresponding osseous contour of the patella don't match in the patellofemoral joint axial plane, but that of the trochlea nearly matches. This is very important for accurately evaluating alignment of patellofemoral joint because the normal osseous alignment of patellofemoral joint don't represent the normal alignment and helpful for designing the part of patellofemoral joint in knee prosthesis.

Diagnosing suspected scaphoid fractures: a systematic review and meta-analysis.

UNLABELLED: Imaging protocols for suspected scaphoid fractures among investigators and hospitals are markedly inconsistent. We performed a systematic review and meta-analysis to assess and compare the diagnostic performance of bone scintigraphy, MRI, and CT for diagnosing suspected scaphoid fractures. Twenty-six studies were included. Sensitivity, specificity, and diagnostic odds ratio were pooled separately and summary receiver operating characteristic curves were fitted for each modality. Meta-regression analyses were performed to compare these modalities. We obtained likelihood ratios derived from the pooled sensitivity and specificity and, using Bayes' theorem, calculated the posttest probability by application of the tests. The pooled sensitivity, specificity, natural logarithm of the diagnostic odds ratio, and the positive and negative likelihood ratios were, respectively, 97%, 89%, 4.78, 8.82, and 0.03 for bone scintigraphy; 96%, 99%, 6.60, 96, and 0.04 for MRI; and 93%, 99%, 6.11, 93, and 0.07 for CT. Bone scintigraphy and MRI have equally high sensitivity and high diagnostic value for excluding scaphoid fracture; however, MRI is more specific and better for confirming scaphoid fracture. We believe additional studies are needed to assess diagnostic performance of CT, especially paired design studies or randomized controlled trials to compare CT with MRI or bone scintigraphy. LEVEL OF EVIDENCE: Level III, diagnostic study. See the Guidelines for Authors for a complete description of levels of evidence.

[The anatomical study of safe zones of the screw fixations in acetabular revision surgery].

OBJECTIVE: To evaluate the safe zones of screw fixations of Jumbo cup and reinforcement rings in acetabular revision surgery. METHODS: From December 2006 to January 2008, 11 fresh frozen human cadaver pelvises were prepared by removing all soft tissues except the medial neurovascular structures, each specimen was held in supine position with clamps. The anteroposterior radiographs were taken after the Jumbo cups or reinforcement rings were fixed in places. Left sides of acetabulum were used to create the models to evaluate the safe zones of the high hip center and Jumbo cups. Right sides were used to evaluate the safe zones of 3 different designs of acetabular reinforcement rings (Müller, Ganz, Burch-Schneider cage). RESULTS: Jumbo cups: screws in the superoanterior and anteroinferior quadrants could cause neurovascular injuries. High hip center: neurovascular injuries could be expected in all quadrants except the inferoposterior and posterior half of superoposterior quadrant. Müller ring: screws placed in the intra-acetabular and extra-acetabular areas of the superoanterior quadrant could cause neurovascular injuries. Ganz ring:the screws placed in superoanterior quadrant and apex area were dangerous. The insults were confirmed in all of the specimens. Burch-Schneider cage: the medial nervous and vasculature structures were injured in all of the specimens if the screws placed in the superoanterior (intra-acetabular and extra-acetabular) quadrant. Screws for ischial fixation could cause sciatic nerve injury. CONCLUSIONS: In revision acetabular surgery, the superoanterior quadrant, the anterior half of the superoposterior quadrant and the implant's central area are unsafe for screw fixation, especially when the exposed thread is longer than 15 mm.

The E-cadherin (CDH1)--160 C/A polymorphism and prostate cancer risk: a meta-analysis.

Published data on the association between E-cadherin (CDH1) -160 C/A polymorphism and prostate cancer (PCA) risk are inconclusive. To derive a more precise estimation of the relationship, a meta-analysis was performed. A logistic regression approach proposed for molecular association studies was used to estimate a biological model of the gene effect. A total of 11 studies including 2637 cases and 2673 controls were involved in this meta-analysis. Logistic regression analysis indicated that the CDH1 -160 C/A genotypes were associated with PCA risk. The genetic model test indicated that the genetic model was most likely to be dominant (CA+AA vs CC). Overall, meta-analysis indicated that the -160A allele carriers (CA+AA) had a 21% elevated risk of PCA, when compared with the homozygotes (CC) (odds ratio (OR)=1.21; 95% confidence interval (CI): 0.97-1.51; P=0.090, P(heterogeneity)=0.001). In the subgroup analyses by ethnicity, significantly elevated risks were associated with -160 variant genotypes (CA+AA) in both European and Asian populations (OR=1.24; 95% CI: 1.08-1.43; P=0.003, P(heterogeneity)=0.220 and OR=1.54; 95% CI: 1.23-1.93; P<0.001, P(heterogeneity)=0.200). However, no significant associations were found in Africans (OR=0.59; 95% CI: 0.32-1.09; P=0.090, P(heterogeneity)=0.070). Although some modest bias could not be eliminated, this meta-analysis suggests that the CDH1 -160A allele is a low-penetrant risk factor for developing PCA, especially in Europeans and Asians.

Treatment of acute scaphoid fractures: systematic review and meta-analysis.

Whether operative treatment is a better option than nonoperative treatment for acute nondisplaced or minimally displaced fractures of the scaphoid is controversial. The type of cast that should be used for nonoperative treatment is not known. We performed a systematic review and meta-analysis of randomized and quasirandomized trials to evaluate the effect of operative versus nonoperative treatment and the effect of different casting methods for nonoperative treatment of acute scaphoid fractures on nonunion rate, return to work, grip strength, range of wrist motion, complications, patient evaluation, and incidence of osteoarthritis. Two investigators assessed trial quality and extracted data. Operative treatment of acute nondisplaced or minimally displaced fractures of the scaphoid waist does not provide greater benefits regarding nonunion rate, return to work, grip strength, range of wrist motion, or patient satisfaction than cast immobilization; however, it causes more complications and, perhaps, a higher risk of scaphotrapezial osteoarthritis. There is no evidence from randomized trials to determine whether operative treatment is superior to nonoperative treatment for an acute proximal pole fracture of scaphoid bones. There is insufficient evidence to determine which type of cast should be used in nonoperative treatment of nondisplaced scaphoid fractures.

[Development of a pathological information network and image analysis system].

This paper introduces a pathological information network and image analysis system designed by ourselves. The system offers an efficient means for modern medical diagnosis and treatment, teaching, research and management in the department of pathology.

[The WHO (1997) classification of 370 cases of malignant lymphomas].

OBJECTIVE: To reclassify retrospectively 370 cases of malignant lymphomas. METHODS: According to the WHO new classification, the clinical features and pathology as well as immunophenotype of 370 lymphomas were analysed. RESULTS: In the 370 lymphomas, there were 359 non-Hodgkin's lymphomas (NHL) (97.03%) and 11 Hodgkin's lymphomas (HL) (2.97%). Of the 359 NHL, 246 were B-cell lymphomas (68.52%), 108 T-cell lymphomas (30.08%), 1 each histiocytic lymphoma and follicular dendritic cell sarcoma, and 3 NK cell lymphomas. The extranodal lymphomas were 196 cases (54.6%) and the nodal lymphomas 163 cases (45.4%). The incidence of NHL categories were in proper order as follows: diffuse large B cell lymphoma (173 cases, 48.2%) > peripheral T cell lymphoma (54 cases, 15.0%) > mucosa associated lymphoid tissue (MALT) lymphoma (31 cases, 8.6%) > NK/T cell lymphoma (25 cases, 7.0%) > follicular lymphoma (21 cases, 5.8%) > anaplastic large cell lymphoma (12 cases, 3.3%). CONCLUSION: The results suggested that the study of malignant lymphomas with WHO new classification have important clinical significance.

[Overexpression of c-erbB-2 and hypoexpression of nm23 relating to poor prognosis of colorectal carcinoma].

OBJECTIVE: To investigate the relationship between expression of c-erbB-2, CD44v6 and nm23 gene proteins and the clinicopathological features of colorectal carcinomas. METHODS: Immunohistochemical technique was adopted to detect the protein expression of c-erbB-2, CD44v6 and nm23 genes in 92 cases of colorectal carcinomas. Of the 92 cases, 28 cases were followed up for more than 10 years, in which the prognosis was analyzed. RESULTS: Expression of c-erbB-2 and CD44v6 was correlating with UICC staging (P < 0.05), and c-erbB-2 was associated with prominent peritumoral lymphocytic infiltration (P < 0.05). In the 28 cases with followed-up data, univariant analysis revealed that the survival rate was correlated with histological grading, UICC staging, tumor growth pattern, peritumoral lymphocytic infiltration, and expression of c-erbB-2, CD44v6 and nm23. However, Cox stepwise proportional hazards analysis showed that only UICC staging, c-erbB-2 and nm23 status retained significant independently in prospecting prognosis. CONCLUSIONS: Besides UICC III and IV stage, overexpression of c-erbB-2 and decreased expression of nm23 are considered acceptable as the parameters in predicting of poor prognosis in colorectal carcinoma.