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1.  Use of herbal medicinal products among children and adolescents in Germany 
Germany is a country with a high use of herbal medicinal products. Population-based data on the use of herbal medicinal products among children are lacking. The aim of this study is to investigate the prevalence, patterns and determinants of herbal medicine use among children and adolescents in Germany.
As data base served the German Health Interview and Examination Survey for Children and Adolescents (KiGGS), a representative population based survey conducted 2003–2006 by the Robert Koch Institute. 17,450 boys and girls aged 0–17 years provided information on drug use in the preceding seven days. Herbal medicinal products were defined according to the European and German drug laws. SPSS Complex Sample method was used to estimate prevalence rates and factors associated with herbal medicine use.
The prevalence rate of herbal medicinal product use amounts to 5.8% (95% confidence interval 5.3-6.3%). Use of herbal medicine declines along with increasing age and shows no difference between boys and girls in younger age groups. Teenage girls are more likely to use herbal medicines than teenage boys. Two thirds of herbal medicines are used for the treatment of coughs and colds; nearly half of herbal medicines are prescribed by medical doctors. Determinants of herbal medicinal product use are younger age, residing in South Germany, having a poor health status, having no immigration background and coming from a higher social class family. Children’s and parents-related health behavior is not found to be associated with herbal medicine use after adjusting for social class.
Use of herbal medicinal products among children and adolescents between the ages of 0 and 17 years in Germany is widely spread and shows relatively higher rates compared to international data. This study provides a reference on the use of herbal medicinal products for policy-makers, health professionals and parents. Further studies are needed to investigate the effectiveness and safety of specific herbal medicinal products, potential effects of long term use as well as possible interactions of herbal medicinal products with concomitantly used conventional medicines.
PMCID: PMC4091953  PMID: 24988878
Herbal medicinal products; Children; KiGGS; Germany
2.  Efficient gene delivery system mediated by cis-aconitate-modified chitosan-g-stearic acid micelles 
Cis-aconitate-modified chitosan-g-stearic acid (CA-CSO-SA) micelles were synthesized in this study to improve the gene transfection efficiency of chitosan-g-stearic acid (CSO-SA). The CA-CSO-SA micelles had a similar size, critical micelle concentration, and morphology, but their zeta potential and cytotoxicity were reduced compared with CSO-SA micelles. After modification with cis-aconitate, the CA-CSO-SA micelles could also compact plasmid DNA (pDNA) to form nanocomplexes. However, the DNA binding ability of CA-CSO-SA was slightly reduced compared with that of CSO-SA. The transfection efficiency mediated by CA-CSO-SA/pDNA against HEK-293 cells reached up to 37%, and was much higher than that of CSO-SA/pDNA (16%). Although the cis-aconitate modification reduced cellular uptake kinetics in the initial stages, the total amount of cellular uptake tended to be the same after 24 hours of incubation. An endocytosis inhibition experiment showed that the internalization mechanism of CA-CSO-SA/pDNA in HEK-293 cells was mainly via clathrin-mediated endocytosis, as well as caveolae-mediated endocytosis and macropinocytosis. Observation of intracellular trafficking indicated that the CSO-SA/pDNA complexes were trapped in endolysosomes, but CA-CSO-SA/pDNA was more widely distributed in the cytosol. This study suggests that modification with cis-aconitate improves the transfection efficiency of CSO-SA/pDNA.
PMCID: PMC4069129  PMID: 24971010
chitosan-g-stearic acid; cis-aconitate; micelles; transfection efficiency; intracellular trafficking
3.  Acute and subacute toxicity study of 1,8-cineole in mice 
The effects of acute and subacute toxicity of 1,8-cineole in Kunming mice were studied. After acute oral administration, the LD50 value (95% CL) was 3849 mg/kg (3488.8~4247.1 mg/kg). In the subacute toxicity study, there were no significant differences in body weight and relative organ weight between the control group and 1,8-cineole treatment groups. The histopathological examinations showed that granular degeneration and vacuolar degeneration appeared in liver and kidney tissue after administration of high dose of 1,8-cineole. Under electron microscopy, a series of ultrastructural changes were observed: The electron microscopy assays indicated that the influence of 1,8-cineole on the target organ at the subcellular level were mainly on the mitochondria, endoplasmic reticulum and other membrane type structure of liver and kidney.
PMCID: PMC4014229  PMID: 24817945
1; 8-cineole; toxicity; histopathology; ultrastructural changes; mice
4.  Area Level Deprivation Is an Independent Determinant of Prevalent Type 2 Diabetes and Obesity at the National Level in Germany. Results from the National Telephone Health Interview Surveys ‘German Health Update’ GEDA 2009 and 2010 
PLoS ONE  2014;9(2):e89661.
There is increasing evidence that prevention programmes for type 2 diabetes mellitus (T2DM) and obesity need to consider individual and regional risk factors. Our objective is to assess the independent association of area level deprivation with T2DM and obesity controlling for individual risk factors in a large study covering the whole of Germany.
We combined data from two consecutive waves of the national health interview survey ‘GEDA’ conducted by the Robert Koch Institute in 2009 and 2010. Data collection was based on computer-assisted telephone interviews. After exclusion of participants <30 years of age and those with missing responses, we included n = 33,690 participants in our analyses. The outcome variables were the 12-month prevalence of known T2DM and the prevalence of obesity (BMI ≥30 kg/m2). We also controlled for age, sex, BMI, smoking, sport, living with a partner and education. Area level deprivation of the districts was defined by the German Index of Multiple Deprivation. Logistic multilevel regression models were performed using the software SAS 9.2.
Of all men and women living in the most deprived areas, 8.6% had T2DM and 16.9% were obese (least deprived areas: 5.8% for T2DM and 13.7% for obesity). For women, higher area level deprivation and lower educational level were both independently associated with higher T2DM and obesity prevalence [highest area level deprivation: OR 1.28 (95% CI: 1.05–1.55) for T2DM and OR 1.28 (95% CI: 1.10–1.49) for obesity]. For men, a similar association was only found for obesity [OR 1.20 (95% CI: 1.02–1.41)], but not for T2DM.
Area level deprivation is an independent, important determinant of T2DM and obesity prevalence in Germany. Identifying and targeting specific area-based risk factors should be considered an essential public health issue relevant to increasing the effectiveness of diabetes and obesity prevention.
PMCID: PMC3937320  PMID: 24586945
5.  Glutathione S-transferase Mu 2-transduced mesenchymal stem cells ameliorated anti-glomerular basement membrane antibody-induced glomerulonephritis by inhibiting oxidation and inflammation 
Oxidative stress is implicated in tissue inflammation, and plays an important role in the pathogenesis of immune-mediated nephritis. Using the anti-glomerular basement membrane antibody-induced glomerulonephritis (anti-GBM-GN) mouse model, we found that increased expression of glutathione S-transferase Mu 2 (GSTM2) was related to reduced renal damage caused by anti-GBM antibodies. Furthermore, mesenchymal stem cell (MSC)-based therapy has shed light on the treatment of immune-mediated kidney diseases. The aim of this study was to investigate if MSCs could be utilized as vehicles to deliver the GSTM2 gene product into the kidney and to evaluate its potential therapeutic effect on anti-GBM-GN.
The human GSTM2 gene (hGSTM2) was transduced into mouse bone marrow-derived MSCs via a lentivirus vector to create a stable cell line (hGSTM2-MSC). The cultured hGSTM2-MSCs were treated with 0.5mM H2O2, and apoptotic cells were measured by terminal dUTP nick-end labeling (TUNEL) assay. The 129/svj mice, which were challenged with anti-GBM antibodies, were injected with 106 hGSTM2-MSCs via the tail vein. Expression of hGSTM2 and inflammatory cytokines in the kidney was assayed by quantitative PCR and western blotting. Renal function of mice was evaluated by monitoring proteinuria and levels of blood urea nitrogen (BUN), and renal pathological changes were analyzed by histochemistry. Immunohistochemical analysis was performed to measure inflammatory cell infiltration and renal cell apoptosis.
MSCs transduced with hGSTM2 exhibited similar growth and differentiation properties to MSCs. hGSTM2-MSCs persistently expressed hGSTM2 and resisted H2O2-induced apoptosis. Upon injection into 129/svj mice, hGSTM2-MSCs migrated to the kidney and expressed hGSTM2. The anti-GBM-GN mice treated with hGSTM2-MSCs exhibited reduced proteinuria and BUN (58% and 59% reduction, respectively) and ameliorated renal pathological damage, compared with control mice. Mice injected with hGSTM2-MSCs showed alleviated renal inflammatory cell infiltration and reduced expression of chemokine (C-C motif) ligand 2 (CCL2), interleukin (IL)-1β and IL-6 (53%, 46% and 52% reduction, respectively), compared with controls. Moreover, hGSTM2-MSCs increased expression of renal superoxide dismutase and catalase, which may associate with detoxifying reactive oxygen species to prevent oxidative renal damage.
Our data suggest that the enhanced protective effect of GSTM2-transduced MSCs against anti-GBM-GN might be associated with inhibition of oxidative stress-induced renal cell apoptosis and inflammation, through over-expression of hGSTM2 in mouse kidneys.
PMCID: PMC4055015  PMID: 24480247
6.  CT-Guided Sclerotherapy for Simple Renal Cysts: Value of Ethanol Concentration Monitoring 
Korean Journal of Radiology  2014;15(1):80-86.
The aim of our study was to evaluate the differences between sclerotherapy with and without ethanol concentration monitoring for the treatment of simple renal cysts.
Materials and Methods
Sixty-seven patients with 70 simple renal cysts were randomly assigned to two groups in a 12-month prospective controlled trial. One group (group A) was treated with computed tomography (CT)-guided sclerotherapy without ethanol concentration monitoring (33 patients with 35 cysts), whereas the other group (group B) had ethanol concentration monitoring (34 patients with 35 cysts) during the procedure. Treatment outcomes between the two groups were compared 12 months later with follow-up ultrasound examination.
After the 12-month follow-up period, the overall success rate was 74.3% in group A and 94.3% in group B (p = 0.022). The mean cyst size before and after treatment was 8.6 ± 2.0 cm and 2.3 ± 2.9 cm, respectively, in group A, and 8.4 ± 1.7 cm and 0.8 ± 1.9 cm, respectively, in group B. The final size of the cysts in group B was significantly smaller than that in group A (p = 0.015). The likelihood of treatment with ethanol concentration monitoring being successful was approximately 16 times higher than without ethanol concentration monitoring (p = 0.026; odds ratio = 15.7; 95% confidence interval: 1.38-179.49). There were no major complications in either group.
Monitoring of Hounsfield units (HU) of ethanol by CT is an effective method in the treatment of simple renal cysts with ethanol sclerotherapy. The ethanol sclerotherapy procedure can be terminated at the point of clear fluid aspiration because the HU (-190) of CT scan corresponds to it.
PMCID: PMC3909866  PMID: 24497796
Simple renal cyst; Ethanol-Sclerotherapy; Computed tomography; Interventional radiology
7.  Preliminary Study on Hepatocyte-Targeted Phosphorus-31 MRS Using ATP-Loaded Galactosylated Chitosan Oligosaccharide Nanoparticles 
Background. The clinical applications of hepatic phosphorus-31 magnetic resonance spectroscopy (31P MRS) remain to be difficult because the changes of phosphates between normal hepatic tissues and pathological tissues are not so obvious, and furthermore, up to now there is few literature on hepatocyte-targeted 31P MRS. Materials and Methods. The ATP-loaded Gal-CSO (Gal-CSO/ATP) nanoparticles were prepared and the special cellular uptake of them as evaluated by using HepG-2 tumor cells and A549 tumor cells, respectively. Two kinds of cells were incubated with the nanoparticles suspension, respectively. Then were prepared the cell samples and the enhancement efficiency of ATP peaks detected by 31P MRS was evaluated. Results. The cellular uptake rate of Gal-CSO/ATP nanoparticles in HepG-2 cells was higher than that in A549 cells. Furthermore, the enlarged ATP peaks of Gal-CSO/ATP nanoparticles in HepG-2 cells were higher than those in A549 cells in vitro detected by 31P MRS. Conclusions. Gal-CSO/ATP nanoparticles have significant targeting efficiency in hepatic cells in vitro and enhancement efficiency of ATP peaks in HepG-2 cells. Furthermore, 31P MRS could be applied in the research of hepatic molecular imaging.
PMCID: PMC3865721  PMID: 24363667
8.  Study on the antiulcer effects of Veronicastrum axillare on gastric ulcer in rats induced by ethanol based on tumor necrosis factor-α (TNF-α) and endothelin-1 (ET-1) 
To assess whether Veronicastrum axillare (V. axillare) can ameliorate ethanol-induced gastric mucosal lesions in rats, reduce the production of pro-inflammatory cytokines, suppress apoptosis and improve local microcirculation disturbances.
Totally 48 male Sprague-Dawley rats were randomly divided into six groups, eight rats in each group. Rats in the normal group and the model group were administered with 0.9% normal saline respectively. Rats in the positive group and ranitidine group were administered with 0.18% ranitidine suspension by intragastric administration respectively. Those in the high dose V. axillare group, the medium dose V. axillare group and the low dose V. axillare group were administrated with V. axillare at the daily dose of 2.8 g/kg, 1.4 g/kg and 0.7 g/kg by intragastric administration. Gastric mucosal lesions were produced by intragastric administration of absolute ethanol. Water extract of V. axillare was successively injected for 14 d and last day was injected 1 h before ethanol administration. Gastric mucosal ulcer index and ulcer inhibitory rate were counted by improved Guth methods. The tissue sections were made for pathological histology analysis. Also, we measured the concentrations of tumor necrosis factor-α (TNF-α) and endothelin-1 (ET-1) in gastric mucosal, as an index of the pro-inflammatory cytokines, apoptosis and local microcirculation. Besides, the mRNA contents of TNF-α and ET-1 were measured to verify effects on gene expression by real-time fluorescent quantitative PCR.
Water extract of V. axillare significantly ameliorated the gastric mucosal lesions induced by ethanol administration (P<0.01). Pro-inflammatory cytokines, TNF-α and ET-1 were increased after ethanol administration and significantly reduced by water extract of V. axillare. The expressions of TNF-α and ET-1 mRNA were also be inhibited by water extract of V. axillare.
Current evidences show water extract of V. axillare is effective for defending against ethanol-induced gastric mucosal lesions, significantly inhibiting the production of pro-inflammatory cytokines and the expressions of TNF-α and ET-1 mRNA, which may be useful for inhibiting apoptosis and improving local microcirculation.
PMCID: PMC3804741  PMID: 24093781
Veronicastrum axillare (Sieb. et Zucc) Yamazaki; Gastric mucosal lesions; Pro-inflammatory cytokines; TNF-α, ET-1
9.  Anti-tumour activity of longikaurin A (LK-A), a novel natural diterpenoid, in nasopharyngeal carcinoma 
Longikaurin A is a natural ent-kaurene diterpenoid isolated from Isodon genus. The ent-kaurene diterpenoids isolated from medicinal plants have been shown to have anti-disease effects. The present study was designed to examine the anti-tumour effects of longikaurin A (LK-A) in nasopharyngeal carcinoma in vitro and in vivo.
Apoptosis and cell cycle arrest were determined by flow cytometry analysis of the cells treated with Longikaurin A. The proteins of apoptosis signaling pathway were detected by western blotting analysis. Finally, we examined whether LK-A exhibits anti-tumour activity in xenograft models.
Longikaurin A inhibited the cell growth by inducing apoptosis and cell cycle arrest. At low concentrations, longikaurin A induced S phase arrest and at higher concentrations, longikaurin A induced caspase-dependent apoptosis by regulating apoptotic molecules. Finally, longikaurin A significantly inhibited the tumour growth of CNE2 xenografts in vivo and showed no obvious effect on the body weights of the mice.
Our results suggest that Longikaurin A exhibited anti-tumour activity in nasopharyngeal carcinoma in vitro and in vivo.
PMCID: PMC3847153  PMID: 23985029
Longikaurin A (LK-A); Apoptosis; Caspase; Nasopharyngeal carcinoma
11.  Preparation and characteristics of lipid nanoemulsion formulations loaded with doxorubicin 
Safe and effective lipid nanoemulsion (LNE) formulations for the antitumor delivery of doxorubicin is designed.
LNEs composed of medium-chain triglyceride, soybean oil, lecithin, and doxorubicin are prepared by a solvent-diffusion method in an aqueous system. The effects of lipid material composition and polyethylene glycol (PEG)ylation on the size, drug encapsulation efficiency, and stability of LNEs are investigated. Based on in-vitro cytotoxicity and cellular uptake tests of A549 (human lung carcinoma) cells, in-vivo biodistribution, antitumor activity, and cardiac toxicity are further examined using nude mouse bearing A549 tumor.
The LNE size decreases from 126.4 ± 8.7 nm to 44.5 ± 9.3 nm with increased weight ratio of medium-chain triglyceride to soybean oil from 1:4 to 3:2, whereas the encapsulation efficiency of doxorubicin is slightly reduced from 79.2% ± 2.1% to 71.2% ± 2.9%. The PEGylation of LNE by 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N-[carboxy(PEG)2000] (DSPE-PEG 2000) does not significantly change the size and drug encapsulation efficiency. Three-month storage at room temperature and lyophilization process does not affect the drug encapsulation efficiency, whereas the size slightly increases to almost 100 nm. The in-vitro drug-release profiles of LNEs suggest that the present formulation can prolong drug release for 48 hours. LNEs can be internalized into tumor cells in vitro and efficiently accumulate in tumor tissues in vivo by passive targeting. Analysis results of in-vitro and in-vivo antitumor activities reveal that doxorubicin-loaded LNE exerts a therapeutic effect similar to that of the commercial Adriamycin. Moreover, the toxicity of doxorubicin, particularly its cardiac toxicity, is reduced.
The present LNE formulation of doxorubicin can effectively suppress tumor growth and improve the safety of Adriamycin.
PMCID: PMC3753155  PMID: 23990722
PEGylation; stability; antitumor activity
12.  A method for energy window optimization for quantitative tasks that includes the effects of model-mismatch on bias: application to 90Y bremsstrahlung SPECT imaging 
Physics in medicine and biology  2012;57(12):3711-3725.
Quantitative Yttrium-90 (90Y) bremsstrahlung SPECT imaging has shown great potential to provide reliable estimates of90Y activity distribution for targeted radionuclide therapy (TRT) dosimetry applications. One factor that potentially affects the reliability of the activity estimates is the choice of the acquisition energy window. In contrast to imaging conventional gamma photon emitters where the acquisition energy windows are usually placed around photopeaks, there has been great variation in the choice of the acquisition energy window for90Y imaging due to the continuous and broad energy distribution of the bremsstrahlung photons. In quantitative imaging of conventional gamma photon emitters, previous methods for optimizing the acquisition energy window assumed unbiased estimators and used the variance in the estimates as a figure-of-merit (FOM). However, for situations, such as90Y imaging, where there are errors in the modeling of the image formation process used in the reconstruction there will be bias in the activity estimates. In90Y bremsstrahlung imaging this will be especially important due to the high levels of scatter, multiple scatter, and collimator septal penetration and scatter. Thus variance will not be a complete measure of reliability of the estimates and thus is not a complete FOM. To address this, we first aimed to develop a new method to optimize the energy window that accounts for both the bias due to model-mismatch and the variance of the activity estimates. We applied this method to optimize the acquisition energy window for quantitative90Y bremsstrahlung SPECT imaging in microsphere brachytherapy. Since absorbed dose is defined as the absorbed energy from the radiation per unit mass of tissues, in this new method we proposed a mass-weighted root mean squared error (RMSE) of the volume of interest (VOI) activity estimates as the FOM. To calculate this FOM, two analytical expressions were derived for calculating the bias due to model-mismatch and the variance of the VOI activity estimates, respectively. To obtain the optimal acquisition energy window for general situations of interest in clinical90Y microsphere imaging, we generated phantoms with multiple tumors of various sizes and various tumor-to-normal activity concentration ratios using a digital phantom that realistically simulates human anatomy, simulated90Y microsphere imaging with a clinical SPECT system and typical imaging parameters using a previously validated Monte Carlo (MC) simulation code, and used a previously-proposed method for modeling the image degrading effects in quantitative SPECT reconstruction. The obtained optimal acquisition energy window was 100–160 keV. The values of the proposed FOM were much larger than the FOM taking into account only the variance of the activity estimates, thus demonstrating in our experiment that the bias of the activity estimates due to model-mismatch was a more important factor than the variance in terms of limiting the reliability of activity estimates.
PMCID: PMC3739432  PMID: 22617760
13.  Ternary nanoparticles composed of cationic solid lipid nanoparticles, protamine, and DNA for gene delivery 
The objective of this research was to design an effective gene delivery system composed of cationic solid lipid nanoparticles (SLNs), protamine, and Deoxyribonucleic acid DNA.
Cationic SLNs were prepared using an aqueous solvent diffusion method with octadecylamine as the cationic lipid material. First, protamine was combined with DNA to form binary protamine/DNA nanoparticles, and the ternary nanoparticle gene delivery system was then obtained by combining binary protamine/DNA nanoparticles with cationic SLNs. The size, zeta potential, and ability of the binary and ternary nanoparticles to compact and protect DNA were characterized. The effect of octadecylamine content in SLNs and the SLNS/DNA ratios on transfection efficiency, cellular uptake and cytotoxicity of the ternary nanoparticles were also assessed using HEK293 cells.
When the weight ratio of protamine to DNA reached 1.5:1, the plasmid DNA could be effectively compacted and protected. The average hydrodynamic diameter of the ternary nanoparticles when combined with protamine increased from 188.50 ± 0.26 nm to 259.33 ± 3.44 nm, and the zeta potential increased from 25.50 ± 3.30 mV to 33.40 ± 2.80 mV when the weight ratio of SLNs to DNA increased from 16/3 to 80/3. The ternary nanoparticles showed high gene transfection efficiency compared with Lipofectamine™ 2000/DNA nanoparticles. Several factors that might affect gene transfection efficiency, such as content and composition of SLNs, post-transfection time, and serum were examined. The ternary nanoparticles composed of SLNs with 15 wt% octadecylamine (50/3 weight ratio of SLNs to DNA) showed the best transfection efficiency (26.13% ± 5.22%) in the presence of serum. It was also found that cellular uptake of the ternary nanoparticles was better than that of the SLN/DNA and binary protamine/DNA nanoparticle systems, and DNA could be transported to the nucleus.
SLNs enhanced entry of binary protamine/DNA nanoparticles into the cell, and protamine protected DNA from enzyme degradation and transported DNA into the nucleus. Compared with Lipofectamine 2000/DNA nanoparticles, these cationic ternary nanoparticles showed relatively durable and stable gene transfection in the presence of serum.
PMCID: PMC3753151  PMID: 23990715
solid lipid nanoparticles; protamine; plasmid DNA; gene transfection; ternary nanoparticles
14.  Galactosylated Chitosan Oligosaccharide Nanoparticles for Hepatocellular Carcinoma Cell-Targeted Delivery of Adenosine Triphosphate 
Nanoparticles composed of galactosylated chitosan oligosaccharide (Gal-CSO) and adenosine triphosphate (ATP) were prepared for hepatocellular carcinoma cell-specific uptake, and the characteristics of Gal-CSO/ATP nanoparticles were evaluated. CSO/ATP nanoparticles were prepared as a control. The average diameter and zeta potential of Gal-CSO/ATP nanoparticles were 51.03 ± 3.26 nm and 30.50 ± 1.25 mV, respectively, suggesting suitable properties for a drug delivery system. Subsequently, the cytotoxicity of Gal-CSO/ATP nanoparticles were examined by the methyl tetrazolium (MTT) assay, and the half maximal inhibitory concentration (IC50) values were calculated with HepG2 (human hepatocellular carcinoma cell line) cells. The results showed that the cytotoxic effect of nanoparticles on HepG2 cells was low. In the meantime, it was also found that the Gal-CSO/ATP nanoparticles could be uptaken by HepG2 cells, due to expression of the asialoglycoprotein receptor (ASGP-R) on their surfaces. The presented results indicate that the Gal-CSO nanoparticles might be very attractive to be used as an intracellular drug delivery carrier for hepatocellular carcinoma cell targeting, thus warranting further in vivo or clinical investigations.
PMCID: PMC3759884  PMID: 23899789
galactosylated chitosan oligosaccharide; adenosine triphosphate; nanoparticles; hepatocyte uptake; targeted drug delivery
15.  Kallikrein Transduced Mesenchymal Stem Cells Protect against Anti-GBM Disease and Lupus Nephritis by Ameliorating Inflammation and Oxidative Stress 
PLoS ONE  2013;8(7):e67790.
Previously we have shown that kallikreins (klks) play a renoprotective role in nephrotoxic serum induced nephritis. In this study, we have used mesenchymal stem cells (MSCs) as vehicles to deliver klks into the injured kidneys and have measured their therapeutic effect on experimental antibody induced nephritis and lupus nephritis. Human KLK-1 (hKLK1) gene was transduced into murine MSCs using a retroviral vector to generate a stable cell line, hKLK1-MSC, expressing high levels of hKLK1. 129/svj mice subjected to anti-GBM induced nephritis were transplanted with 106 hKLK1-MSCs and hKLK1 expression was confirmed in the kidneys. Compared with vector-MSCs injected mice, the hKLK1-MSCs treated mice showed significantly reduced proteinuria, blood urea nitrogen (BUN) and ameliorated renal pathology. Using the same strategy, we treated lupus-prone B6.Sle1.Sle3 bicongenic mice with hKLK1-MSCs and demonstrated that hKLK1-MSCs delivery also attenuated lupus nephritis. Mechanistically, hKLK1-MSCs reduced macrophage and T-lymphocyte infiltration into the kidney by suppressing the expression of inflammation cytokines. Moreover, hKLK1 transduced MSCs were more resistant to oxidative stress-induced apoptosis. These findings advance genetically modified MSCs as potential gene delivery tools for targeting therapeutic agents to the kidneys in order to modulate inflammation and oxidative stress in lupus nephritis.
PMCID: PMC3720854  PMID: 23935844
16.  Genetic Polymorphisms of the CASP8 Gene Promoter May Not Be Associated with Colorectal Cancer in Han Chinese from Southwest China 
PLoS ONE  2013;8(7):e67577.
Caspase 8 (CASP8) plays a critical role in the apoptotic pathway and aberrant regulation of this pathway causes many diseases including cancers. Genetic variants rs3834129 (CTTACT/−) and rs3769821 (T/C) in the promoter region of the CASP8 gene were documented to be associated with multiple solid cancers and non-Hodgkin’s lymphoma (NHL), respectively, despite of some controversies. We aimed to discern potential association of these two variants and rs113686495 (CTGTCATT/−), as well as CASP8 mRNA and protein expression levels with colorectal cancer (CRC) in Han Chinese.
We genotyped CASP8 genetic variants in 305 CRC patients and 342 healthy individuals from Kunming, Southwest China. Expression levels of CASP8 mRNA and protein were quantified in paired cancerous and paracancerous normal tissues by using real-time quantitative PCR and western blot, respectively. We compared the frequencies of alleles, genotypes, and haplotypes between the cases and controls. Correlation of CASP8 mRNA and protein expression levels in paired cancerous and paracancerous normal tissues from patients with different genotypes and clinical expression were also evaluated.
There was no association of the CASP8 genetic variants with CRC in our case-control study. The CASP8 gene mRNA expression levels in cancerous and paracancerous normal tissues were similar and there was no significant difference between subjects with different genotypes and clinical features. However, we found that CASP8 protein level was significantly lower in cancerous tissues than in paired paracancerous normal tissues.
Our results suggest that the three CASP8 genetic variants may not be associated with CRC risk in Han Chinese from southwest China. Aberrant CASP8 protein expression may play a role in the pathogenesis of CRC.
PMCID: PMC3699664  PMID: 23844036
18.  Thoracic epidural angiolipoma: A case report and review of the literature 
World Journal of Radiology  2013;5(4):187-192.
Angiolipoma of the spine is a benign neoplasm consisting of both mature fatty tissue and abnormal vascular elements, and usually presents with a slow progressive clinical course. Our patient presented with bilateral lower extremity weakness and chest-back numbness. Physical examination revealed adipose elements superficial hypesthesia below the T5 level and analgesia below the T6 level. Magnetic resonance imaging (MRI) scan showed an avidly and heterogeneously enhancing mass which was located in the posterior epidural space. Compression of the thoracic cord by the fusiform mass was seen between T3-T4. During the operation, a flesh pink vascular mass (4.7 cm × 1.0 cm × 1.0 cm) with obscure margin and strong but pliable texture was found in the posterior epidural space extending from T3 to T4. There was no infiltration of the dura or the adjacent bony spine. Histopathological study of the surgical specimen showed a typical angiolipoma. We review the previously documented cases of spinal extradural angiolipomas performed with MRI.
PMCID: PMC3647212  PMID: 23671756
Angiolipoma; Spinal epidural tumor; Spinal cord compression; Histopathology
19.  Magnetic resonance imaging for prostate cancer clinical application 
As prostate cancer is a biologically heterogeneous disease for which a variety of treatment options are available, the major objective of prostate cancer imaging is to achieve more precise disease characterization. In clinical practice, magnetic resonance imaging (MRI) is one of the imaging tools for the evaluation of prostate cancer, the fusion of MRI or dynamic contrast-enhanced MRI (DCE-MRI) with magnetic resonance spectroscopic imaging (MRSI) is improving the evaluation of cancer location, size, and extent, while providing an indication of tumor aggressiveness. This review summarizes the role of MRI in the application of prostate cancer and describes molecular MRI techniques (including MRSI and DCE-MRI) for aiding prostate cancer management.
PMCID: PMC3626986  PMID: 23592906
Prostate cancer; magnetic resonance imaging (MRI); functional MRI; molecular MRI
20.  Serial Non-Invasive Assessment of Antibody Induced Nephritis in Mice Using Positron Emission Tomography 
PLoS ONE  2013;8(2):e57418.
Mouse models of experimental anti-glomerular basement membrane (anti-GBM) nephritis provide an analytical tool for studying spontaneous lupus nephritis. The potential of Positron Emission Tomography (PET) was evaluated using 2-deoxy-2-[18F]fluoro-d-glucose (FDG) as a probe to monitor the progression of anti-GBM induced nephritis in a mouse model. The imaging results were compared to conventional measures of renal function and pathological changes. Serum and urinary vascular cell adhesion molecule-1 (VCAM-1) levels were used as measures of endothelial cell activation and inflammation. Following a challenge with anti-glomerular antibodies, mice exhibited peak changes in serum creatinine, proteinuria, and glomerulonephritis score at 14 days post-challenge (p.c.). In contrast, VCAM levels peaked at day 7 p.c. On dynamic PET images (0–60 min) of day 7, kidneys of the anti-GBM nephritis mice demonstrated a unique pattern of FDG uptake. Compared to the time activity curve (TAC) prior to challenge, a rightward shift was observed after the challenge. By day 10 p.c., kidney FDG uptake was lower than baseline and remained so until the study ended at 21 days p.c. During this time frame measures of renal dysfunction remained high but VCAM-1 levels declined. These changes were accompanied by an increase in kidney volume as measured by Computed Tomography (CT) and intra-abdominal fluid collection. Our results suggest that FDG-PET-CT can be used as a non-invasive imaging tool to longitudinally monitor the progression of renal disease activity in antibody mediated nephritis and the magnitude of renal FDG retention correlates better with early markers of renal inflammation than renal dysfunction.
PMCID: PMC3584026  PMID: 23460853
21.  Prevalence and comorbidity of diabetes mellitus among non-institutionalized older adults in Germany - results of the national telephone health interview survey ‘German Health Update (GEDA)’ 2009 
BMC Public Health  2013;13:166.
Despite the major public health impact of diabetes, recent population-based data regarding its prevalence and comorbidity are sparse.
The prevalence and comorbidity of diabetes mellitus were analyzed in a nationally representative sample (N = 9133) of the non-institutionalized German adult population aged 50 years and older. Information on physician-diagnosed diabetes and 20 other chronic health conditions was collected as part of the national telephone health interview survey ‘German Health Update (GEDA)’ 2009. Overall, 51.2% of contacted persons participated. Among persons with diabetes, diabetes severity was defined according to the type and number of diabetes-concordant conditions: no diabetes-concordant condition (grade 1); hypertension and/or hyperlipidemia only (grade 2); one comorbidity likely to represent diabetes-related micro- or macrovascular end-organ damage (grade 3); several such comorbidities (grade 4). Determinants of diabetes severity were analyzed by multivariable ordinal regression.
The 12-month prevalence of diabetes was 13.6% with no significant difference between men and women. Persons with diabetes had a significantly higher prevalence and average number of diabetes-concordant as well as diabetes-discordant comorbidities than persons without diabetes. Among persons with diabetes, 10.2%, 46.8%, 35.6% and 7.4% were classified as having severity grade 1–4, respectively. Determinants of diabetes severity included age (cumulative odds ratio 1.05, 95% confidence interval 1.03-1.07, per year) and number of discordant comorbidities (1.40, 1.25-1.55). With respect to specific discordant comorbidities, diabetes severity was correlated to depression (2.15, 1.29-3.56), respiratory disease (2.75, 1.72-4.41), musculoskeletal disease (1.53, 1.06-2.21), and severe hearing impairment (3.00, 1.21-7.41).
Diabetes is highly prevalent in the non-institutionalized German adult population 50 years and older. Diabetes comorbidities including diabetes-concordant and diabetes-discordant conditions need to be considered in epidemiological studies, in order to monitor disease burden and quality of diabetes care. Definitional standards of diabetes severity need to be refined and consented.
PMCID: PMC3599814  PMID: 23433228
Diabetes; Prevalence; Comorbidity; Germany
22.  Saikosaponin a Enhances Transient Inactivating Potassium Current in Rat Hippocampal CA1 Neurons 
Saikosaponin a (SSa), a main constituent of the Chinese herb Bupleurum chinense DC., has been demonstrated to have antiepileptic activity. Recent studies have shown that SSa could inhibit NMDA receptor current and persistent sodium current. However, the effects of SSa on potassium (K+) currents remain unclear. In this study, we tested the effect of SSa on 4AP-induced epileptiform discharges and K+ currents in CA1 neurons of rat hippocampal slices. We found that SSa significantly inhibited epileptiform discharges frequency and duration in hippocampal CA1 neurons in the 4AP seizure model in a dose-dependent manner with an IC50 of 0.7 μM. SSa effectively increased the amplitude of ITotal and IA, significantly negative-shifted the activation curve, and positive-shifted steady-state curve of IA. However, SSa induced no significant changes in the amplitude and activation curve of IK. In addition, SSa significantly increased the amplitude of 4AP-sensitive K+ current, while there was no significant change in the amplitude of TEA-sensitive K+ current. Together, our data indicate that SSa inhibits epileptiform discharges induced by 4AP in a dose-dependent manner and that SSa exerts selectively enhancing effects on IA. These increases in IA may contribute to the anticonvulsant mechanisms of SSa.
PMCID: PMC3608310  PMID: 23554830
23.  Distribution of Cell-free and Cell-associated HIV surrogates in the Colon Following Simulated Receptive Anal Intercourse in Men who Have Sex with Men 
Describing the distribution and clearance of HIV surrogates within the gastrointestinal (GI) tract to inform rectal microbicide development.
Radiolabeled, simulated HIV-infected semen was administered, imaged, and biopsied to simulate and measure colonic HIV distribution following anal intercourse.
Healthy male subjects with a history of receptive anal intercourse and experience with the use of anal sex toys were recruited to this study. Apheresis isolated leukocytes were collected prior to simulated intercourse. These autologous leukocytes, radiolabeled with 9.25 MBq 111Indium-oxine (cell-associated HIV surrogate), and sulfur colloid particles, labeled with 37 MBq 99mTechnectium (cell-free HIV surrogate), were mixed in 3 mL autologous seminal plasma. This simulated HIV-infected semen was administered to subjects via an artificial phallus with urethra after 5 minutes of simulated intercourse. Post-dosing, dual isotope SPECT/CT images were acquired at 1, 4, 8, and 24 hours. At 5 hours post-dosing, colon biopsies were collected, CD4 cells were extracted, and samples analyzed for radioactivity.
SPECT/CT images showed similar luminal distribution for both surrogates, with migration limited to the recto-sigmoid colon in all subjects. SPECT showed at least 75% overlap in distribution of both surrogates up to 4 hrs following dosing. Biopsies indicate that 2.4% of CD4 cells extracted from recto-sigmoid colon tissue were exogenously administered.
Our HIV surrogates stayed within the recto-sigmoid colon for 24 hours. Exogenously dosed autologous lymphocytes and HIV-sized particles migrate to similar locations, and associate with the colonic tissue in the lumen.
PMCID: PMC3237874  PMID: 21937920
HIV; Rectal microbicide; Anal intercourse; Sexual transmission; Pharmacokinetics
24.  Modulating proximal cell signaling by targeting Btk ameliorates humoral autoimmunity and end-organ disease in murine lupus 
Arthritis Research & Therapy  2012;14(6):R243.
Systemic lupus erythematosus is a chronic autoimmune disease characterized by an abundance of autoantibodies against nuclear antigens. Bruton's tyrosine kinase (Btk) is a proximal transducer of the BCR signal that allows for B-cell activation and differentiation. Recently, selective inhibition of Btk by PCI-32765 has shown promise in limiting activity of multiple cells types in various models of cancer and autoimmunity. The aim of this study was to determine the effect of Btk inhibition by PCI-32765 on the development of lupus in lupus-prone B6.Sle1 and B6.Sle1.Sle3 mice.
B6.Sle1 or B6.Sle1.Sle3 mice received drinking water containing either the Btk inhibitor PCI-32765 or vehicle for 56 days. Following treatment, mice were examined for clinical and pathological characteristics of lupus. The effect of PCI-32765 on specific cell types was also investigated.
In this study, we report that Btk inhibition dampens humoral autoimmunity in B6.Sle1 monocongenic mice. Moreover, in B6.Sle1.Sle3 bicongenic mice that are prone to severe lupus, Btk inhibition also dampens humoral and cellular autoimmunity, as well as lupus nephritis.
These findings suggest that partial crippling of cell signaling in B cells and antigen presenting cells (APCs) may be a viable alternative to total depletion of these cells as a therapeutic modality for lupus.
PMCID: PMC3674619  PMID: 23136880
25.  Serial Non-Invasive Monitoring of Renal Disease Following Immune-Mediated Injury Using Near-Infrared Optical Imaging 
PLoS ONE  2012;7(9):e43941.
Non-invasive monitoring of disease progression in kidney disease is still a major challenge in clinical practice. In vivo near-infrared (NIR) imaging provides a new tool for studying disease mechanisms and non-invasive monitoring of disease development, even in deep organs. The LI-COR IRDye® 800CW RGD optical probe (RGD probe) is a NIR fluorophore, that can target integrin alpha v beta 3 (αvβ3) in tissues.
This study aims to monitor renal disease progression in an anti-glomerular basement membrane (GBM) nephritis mouse model.
Anti-GBM nephritis was induced in 129x1/svJ mice by anti-GBM serum challenge. The expression of integrin αvβ3 in the diseased kidney was examined by immunohistochemistry and quantitative polymerase chain reaction. The RGD probe and control fluorophores, the 800CW dye, and the BSA-conjugated 800CW dye, were administered into anti-GBM nephritic mice. LI-COR Pearl® Impulse imaging system was used for in vivo imaging; while ex vivo organ imaging was acquired using the MaestroTM imaging system.
Kidney tissue from anti-GBM nephritic mice showed higher levels of integrin αvβ3 expression at both the protein and the mRNA level compared to normal mice. The RGD probe allowed in vivo renal imaging and the fluorescent signal could be specifically captured in the diseased kidneys up to 14 days, reflecting longitudinal changes in renal function.
The infrared RGD molecular probe that tracks integrin expression can be successfully used to monitor renal disease progression following immune-mediated nephritis.
PMCID: PMC3458852  PMID: 23049742

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