TGF-ß1 aggravates degenerative nucleus pulposus cells inflammation and fibrosis through the upregulation of angiopoietin-like protein 2 expression.

OBJECTIVE: Inflammation and fibrosis progress of nucleus pulposus (NP) cells participate in the pathologic changes of intervertebral disc degeneration (IDD). ANGPTL2 is well known for its angiogenesis and proinflammatory properties and transforming growth factor ß1 (TGF-ß1) is also responsible for tissue fibrosis. However, the role of ANGPTL2 in IDD and whether it is related to TGF-ß1 remains unclear. This study aims to explore the relation of TGF-ß1 and ANGPTL2 in the degenerative process of NP cells. PATIENTS AND METHODS: We isolated NP cells of NP tissues provided from the spine fracture patients. IL-1ß was used to induce the NP cells degeneration. To determine the effect of TGF-ß1 and ANGPTL2 on NP cell degeneration, we regulated the cellular TGF-ß1 and ANGPTL2 expression by Recombinant human protein stimulation and siRNA transfection. Quantitative real-time polymerase chain reaction (qRT-PCR) or Western blot was employed to investigate the expression of TGF-ß1, ANGPTL2, IL-6, TNF-α, collagen I, and collagen III. RESULTS: TGF-ß1 overexpression aggravated the ANGPTL2, IL-6, TNF-α, collagen I, and collagen III expressions of NP cells that caused by IL-1ß, which was rejected by ANGPTL2 gene silencing. Besides, the silencing of TGF-ß1 weakened the ANGPTL2 expression. ANGPTL2 overexpression promoted the NP cells inflammation and fibrosis via increasing IL-6, TNF-α, collagen I, and collagen III expression, which was sharpened by a consequent increase of TGF-ß1 expression. CONCLUSIONS: This study, for the first time, points that TGF-ß1 aggravates degenerative NP cells inflammation and fibrosis via the mediation of ANGPTL2.

Risk factors for the treatment outcome of retreated pulmonary tuberculosis patients in China: an optimized prediction model.

Retreatment of tuberculosis (TB) often fails in China, yet the risk factors associated with the failure remain unclear. To identify risk factors for the treatment failure of retreated pulmonary tuberculosis (PTB) patients, we analyzed the data of 395 retreated PTB patients who received retreatment between July 2009 and July 2011 in China. PTB patients were categorized into 'success' and 'failure' groups by their treatment outcome. Univariable and multivariable logistic regression were used to evaluate the association between treatment outcome and socio-demographic as well as clinical factors. We also created an optimized risk score model to evaluate the predictive values of these risk factors on treatment failure. Of 395 patients, 99 (25·1%) were diagnosed as retreatment failure. Our results showed that risk factors associated with treatment failure included drug resistance, low education level, low body mass index (6 months), standard treatment regimen, retreatment type, positive culture result after 2 months of treatment, and the place where the first medicine was taken. An Optimized Framingham risk model was then used to calculate the risk scores of these factors. Place where first medicine was taken (temporary living places) received a score of 6, which was highest among all the factors. The predicted probability of treatment failure increases as risk score increases. Ten out of 359 patients had a risk score >9, which corresponded to an estimated probability of treatment failure >70%. In conclusion, we have identified multiple clinical and socio-demographic factors that are associated with treatment failure of retreated PTB patients. We also created an optimized risk score model that was effective in predicting the retreatment failure. These results provide novel insights for the prognosis and improvement of treatment for retreated PTB patients.

Neuroblastomas vary widely in their sensitivities to herpes simplex virotherapy unrelated to virus receptors and susceptibility.

Although most high-risk neuroblastomas are responsive to chemotherapy, relapse is common and long-term survival is < 40%, underscoring the need for more effective treatments. We evaluated the responsiveness of 12 neuroblastoma cell lines to the Δγ134.5 attenuated oncolytic herpes simplex virus (oHSV), Seprehvir (HSV1716), which is currently used in pediatric phase I trials. We found that entry of Seprehvir in neuroblastoma cells is independent of the expression of nectin-1 and the sum of all four known major HSV entry receptors. We observed varying levels of sensitivity and permissivity to Seprehvir, suggesting that the cellular anti-viral response, not virus entry, is the key determinant of efficacy with this virus. In vivo, we found significant anti-tumor efficacy following Seprehvir treatment, which ranged from 6/10 complete responses in the CHP-134 model to a mild prolonged median survival in the SK-N-AS model. Taken together, these data suggest that anti-tumor efficacy cannot be solely predicted based on in vitro response. Whether or not this discordance holds true for other viruses or tumor types is unknown. Our results also suggest that profiling the expression of known viral entry receptors on neuroblastoma cells may not be entirely predictive of their susceptibility to Seprehvir therapy.

Elevated BDNF mRNA expression in the medial prefrontal cortex after d-amphetamine reinstated conditioned place preference in rats.

Drug addiction behavior that is established and maintained by psychostimulants has been shown to be associated with the expression of brain-derived neurotrophic factor (BDNF) in the mesolimbic dopamine (DA) system. Cocaine has been used for most prior studies testing this effect of psychostimulants and therefore relatively little is known about its counterpart amphetamine (AMP). To fill this gap, the present study was designed to test whether BDNF mRNA expression levels in the DA terminal regions were changed specifically by d-AMP-induced conditioned place preference (CPP) followed by drug-primed reinstatement. The dose of d-AMP, 1mg/kg, was confirmed to significantly induce CPP. Using this dose, a group of rats was initially subjected to d-AMP CPP, which was followed by entry into an extinction protocol with an additional 3-day withdrawal before a drug-primed reinstatement test was carried out. Following extinction of d-AMP CPP, a lower dose of d-AMP, namely 0.75mg/kg, was able to significantly reinstate CPP. The BDNF mRNA levels in the selected brain areas were determined by real-time polymerase chain reaction (PCR) after the CPP and reinstatement. The BDNF mRNA level in the medial prefrontal cortex (mPFC) was significantly increased after the reinstatement, but not the CPP test. And, none of the other four assessed brain areas showed any change in BDNF mRNA level after d-AMP CPP or reinstatement. These findings support the notion that BDNF is involved in drug-seeking behavior and indicate that d-AMP reinstatement after extinction may be linked to an increase in BDNF mRNA expression in the mPFC.

Expression of HSV-1 receptors in EBV-associated lymphoproliferative disease determines susceptibility to oncolytic HSV.

Epstein-Barr virus (EBV)-associated B-cell lymphoproliferative disease (LPD) after hematopoietic stem cell or solid organ transplantation remains a life-threatening complication. Expression of the virus-encoded gene product, EBER, has been shown to prevent apoptosis via blockade of PKR activation. As PKR is a major cellular defense against Herpes simplex virus (HSV), and oncolytic HSV-1 (oHSV) mutants have shown promising antitumor efficacy in preclinical models, we sought to determine whether EBV-LPD cells are susceptible to infection by oHSVs. We tested three primary EBV-infected lymphocyte cell cultures from neuroblastoma (NB) patients as models of naturally acquired EBV-LPD. NB12 was the most susceptible, NB122R was intermediate and NB88R2 was essentially resistant. Despite EBER expression, PKR was activated by oHSV infection. Susceptibility to oHSV correlated with the expression of the HSV receptor, nectin-1. The resistance of NB88R2 was reversed by exogenous nectin-1 expression, whereas downregulation of nectin-1 on NB12 decreased viral entry. Xenografts derived from the EBV-LPDs exhibited only mild (NB12) or no (NB88R2) response to oHSV injection, compared with a NB cell line that showed a significant response. We conclude that EBV-LPDs are relatively resistant to oHSV virotherapy, in some cases, due to low virus receptor expression but also due to intact antiviral PKR signaling.

NAT2 polymorphisms and susceptibility to anti-tuberculosis drug-induced liver injury: a meta-analysis.

BACKGROUND AND OBJECTIVE: Although a series of studies have evaluated the potential association between N-acetyltransferase 2 (NAT2) polymorphisms and the risk of anti-tuberculosis drug-induced liver injury (ATLI), the results have generally been controversial and inadequate, mainly due to limited power. The present meta-analysis sought to resolve this problem. DESIGN: PubMed, Embase and Web of Science were searched using the following key words: 'N-acetyltransferase 2' or 'NAT2' and 'polymorphism' and 'tuberculosis' or 'TB' and 'hepatotoxicity' or 'liver injury'. Crude odds ratios (ORs) with 95% confidence intervals (CIs) were summarised in forest plots and set out in a table. RESULTS: A total of 14 studies, comprising 474 cases and 1446 controls, were included in the meta-analysis. A significant association was observed between NAT2 slow acetylators and the risk of ATLI. The OR for NAT2 slow acetylators compared with rapid acetylators was 4.697 (95%CI 3.291-6.705, P < 0.001). Subgroup analyses indicate that both Asian and non-Asian cases with slow acetylators develop ATLI more frequently, which is similar to patients with slow acetylators receiving first-line combination treatment. On comparing NAT2 intermediate acetylators with rapid acetylators, the OR for ATLI was 1.261 (95%CI 0.928-1.712, P = 0.138). CONCLUSIONS: This meta-analysis showed that tuberculosis patients with slow acetylators had a higher risk of ATLI than other acetylators. Screening of patients for the NAT2 genetic polymorphisms will be useful for the clinical prediction and prevention of ATLI.

Soy isoflavone intake inhibits bone resorption and stimulates bone formation in menopausal women: meta-analysis of randomized controlled trials.

OBJECTIVE: To clarify the effects of isoflavone intake on bone resorption and bone formation. METHODS: We identified randomized controlled trials related to urinary deoxypyridinoline (Dpyr, a bone resorption marker) and serum bone-specific alkaline phosphatase (BAP, a bone formation marker) listed on MEDLINE (January 1966-April 2006), the Cochrane Controlled Trials Register, EMBASE (1985-January 2006), Science Citation Index and PUBMED (updated till April 2006). RESULTS: Nine studies with a total of 432 subjects were selected for meta-analysis. The urinary Dpyr concentration in subjects who consumed isoflavones decreased significantly by -2.08 nmol/mmol (95% confidence interval (CI): -3.82 to -0.34 nmol/mmol) in comparison with that in subjects who did not consume isoflavones. Isoflavone intake vs placebo intake significantly increased serum BAP by 1.48 microg/l (95% CI: 0.22-2.75 mug/l). Decreases in the urinary Dpyr concentration with isoflavone intake of <90 mg/day and with treatment lasting less than 12 weeks were -2.34 nmol/mmol (95% CI: -4.46 to -0.22 nmol/mmol) and -2.03 nmol/mmol (95% CI: -3.20 to -0.85 nmol/mmol), respectively. CONCLUSIONS: Isoflavone intervention significantly inhibits bone resorption and stimulates bone formation. These favorable effects occur even if <90 mg/day of isoflavones are consumed or the intervention lasts less than 12 weeks.

Milk/dairy products consumption, galactose metabolism and ovarian cancer: meta-analysis of epidemiological studies.

Ovarian cancer is the fifth most common cause of cancer death among women and the leading cause of gynaecological cancer death in the United States. Milk/dairy products consumption was considered to be a risk factor for ovarian cancer mainly because milk carbohydrate-lactose and galactose metabolism is toxic to oocytes. However, recent evidence does not support this hypothesis completely. We collected epidemiological studies related to the association between milk/dairy products consumption or galactose metabolism (lactose, galactose, galactose-1-phosphate uridyltransferase, lactose/transferase) and ovarian cancer published between January 1966 and August 2003 and found 27 items from 22 independent studies. Twenty studies were case-control studies and the other two were cohort studies. A meta-analysis method was conducted to estimate relative risk combining all relative data. In general, we did not find any association between milk/dairy products or galactose metabolism and ovarian cancer risk in this meta-analysis. The consumption of whole milk and butter, which contain relatively high amounts of fat, was positively (relative risk > 1.2), but not significantly, associated with an increased risk.

Eliminating spatiotemporal chaos and spiral waves by weak spatial perturbations

The possibility of eliminating spatiotemporal chaos and spiral waves by weak spatial perturbations in a spatially extended dynamical system is demonstrated numerically through the example of a wide-aperture laser. The time-independent weak spatial perturbation can effectively migrate the system from the state of spatiotemporal chaos or spiral waves to that of traveling waves. The threshold and the controllable range of the control parameters are given. By varying the amplitude or the spatial wave vector of the perturbation, drastic changes in the spatiotemporal dynamics are found.