Nonparametric estimation of natural direct and indirect effects based on inverse probability weighting

Using a sequential conditional independence assumption, this paper discusses fully nonparametric estimation of natural direct and indirect causal effects in causal mediation analysis based on inverse probability weighting. We propose estimators of the average indirect effect of a binary treatment, which operates through intermediate variables (or mediators) on the causal path between the treatment and the outcome, as well as the unmediated direct effect. In a first step, treatment propensity scores given the mediator and observed covariates or given covariates alone are estimated by nonparametric series logit estimation. In a second step, they are used to reweigh observations in order to estimate the effects of interest. We establish root-n consistency and asymptotic normality of this approach as well as a weighted version thereof. The latter allows evaluating effects on specific subgroups like the treated, for which we derive the asymptotic properties under estimated propensity scores. We also provide a simulation study and an application to an information intervention about male circumcisions

The absorption and uptake of recombinant human follicle-stimulating hormone through vaginal subcutaneous injections - a pharmacokinetic study

<p>Abstract</p> <p>Background</p> <p>Follicle stimulating hormone (FSH) has been routinely used for ovulation induction. Because of rapid clearance of the hormone, FSH is commonly administered by daily intramuscular or subcutaneous injections in in-vitro fertilization (IVF). To reduce the number of visits to the clinic, an intermittent vaginal injection of rhFSH every 3 days employing the concepts of mesotherapy and uterine first-pass effect was invented and has successfully been applied in women receiving IVF treatment. This study was designed to monitor the pharmacokinetic pattern of rhFSH administered vaginally.</p> <p>Methods</p> <p>Twelve healthy women with regular ovulatory cycles were recruited. All volunteers received gonadotrophin-releasing hormone agonist to suppress pituitary function and were assigned to receive single dose recombinant human FSH (rhFSH, Puregon 300) either using conventional abdominal subcutaneous injection or vaginal subcutaneous injection in a randomized cross-over study. Serum samples were collected at pre- scheduled time intervals after injections of rhFSH to determine immunoreactive FSH levels. Pharmacokinetic parameters characterizing rate [maximal plasma concentrations (Cmax) and time of maximal plasma concentrations (tmax)] and extent [area under the plasma concentration-time curve (AUC) and clearance] of absorption of rhFSH were compared.</p> <p>Results</p> <p>Vaginal injection of rhFSH was well tolerated and no drug-related adverse reaction was noted. Our analysis revealed that tmax was significantly earlier (mean 6.67 versus 13.33 hours) and Cmax was significantly higher (mean 17.77 versus 13.96 IU/L) in vaginal versus abdominal injections. The AUC_0-∞ was 1640 versus 1134 IU·hour/L in vaginal and abdominal injections, respectively. Smaller plasma elimination rate constant (0.011 versus 0.016 hour-1), longer mean residence time (106.58 versus 70.47 hours), and slower total body clearance (292.2 versus 400.1 mL/hour) were also found in vaginal injection.</p> <p>Conclusion</p> <p>The vaginal injection mode elicited a rapid and highly extended absorption of rhFSH injected compared to conventional abdominal injection. These data indicate that the rate and extent of FSH absorption from the injection site can vary depending on the route of the FSH administration.</p

Caffeine and a selective adenosine A2A receptor antagonist induce sensitization and cross-sensitization behavior associated with increased striatal dopamine in mice

<p>Abstract</p> <p>Background</p> <p>Caffeine, a nonselective adenosine A₁and A_2Areceptor antagonist, is the most widely used psychoactive substance in the world. Evidence demonstrates that caffeine and selective adenosine A_2Aantagonists interact with the neuronal systems involved in drug reinforcement, locomotor sensitization, and therapeutic effect in Parkinson's disease (PD). Evidence also indicates that low doses of caffeine and a selective adenosine A_2Aantagonist SCH58261 elicit locomotor stimulation whereas high doses of these drugs exert locomotor inhibition. Since these behavioral and therapeutic effects are mediated by the mesolimbic and nigrostriatal dopaminergic pathways which project to the striatum, we hypothesize that low doses of caffeine and SCH58261 may modulate the functions of dopaminergic neurons in the striatum.</p> <p>Methods</p> <p>In this study, we evaluated the neuroadaptations in the striatum by using reverse-phase high performance liquid chromatography (HPLC) to quantitate the concentrations of striatal dopamine and its metabolites, dihydroxylphenylacetic acid (DOPAC) and homovanilic acid (HVA), and using immunoblotting to measure the level of phosphorylation of tyrosine hydroxylase (TH) at Ser31, following chronic caffeine and SCH58261 sensitization in mice. Moreover, to validate further that the behavior sensitization of caffeine is through antagonism at the adenosine A_2Areceptor, we also evaluate whether chronic pretreatment with a selective adenosine A_2Aantagonist SCH58261 or a selective adenosine A₁antagonist DPCPX can sensitize the locomotor stimulating effects of caffeine.</p> <p>Results</p> <p>Chronic treatments with low dose caffeine (10 mg/kg) or SCH58261 (2 mg/kg) increased the concentrations of dopamine, DOPAC and HVA, concomitant with increased TH phosphorylation at Ser31 and consequently enhanced TH activity in the striatal tissues in both caffeine- and SCH58261-sensitized mice. In addition, chronic caffeine or SCH58261 administration induced locomotor sensitization, and locomotor cross-sensitization to caffeine was observed following chronic treatment of mice with SCH58261 but not with DPCPX.</p> <p>Conclusions</p> <p>Our study demonstrated that low dosages of caffeine and a selective adenosine A_2Aantagonist SCH58261 elicited locomotor sensitization and cross-sensitization, which were associated with elevated dopamine concentration and TH phosphorylation at Ser31 in the striatum. Blockade of adenosine A_2Areceptor may play an important role in the striatal neuroadaptations observed in the caffeine-sensitized and SCH58261-sensitized mice.</p

Ultrasound-Guided Glenohumeral Joint Injection Using the Posterior Approach

Injection treatment to the glenohumeral joint is often needed to treat shoulder problems such as adhesive capsulitis. This can be done through blind palpation technique and fluoroscopic or musculoskeletal ultrasound guidance. In recent years, ultrasound has been proven to increase the accuracy of needle placement into the glenohumeral joint. Ultrasound is radiation free and offers real-time images in performing needle-guided injection procedures. Glenohumeral joint injection can be done using the anterior rotator interval approach or the posterior approach technique. Both techniques are generally well tolerated by the patients. However, it was shown that the posterior injection technique offers an easier and a more effective approach to the glenohumeral joint with less extravasation rate as compared with the anterior approach. The posterior approach also avoids the potential risk of accidental puncture or injection into the axillary neurovascular structures. A linear transducer of 5–12 MHz is usually used. This technique is often applied to inject corticosteroid for the treatment of frozen shoulder or contrast medium for computed tomography or magnetic resonance shoulder arthrography

AMP-activated protein kinase activation mediates CCL3-induced cell migration and matrix metalloproteinase-2 expression in human chondrosarcoma

Chemokine (C-C motif) ligand 3 (CCL3), also known as macrophage inflammatory protein-1α, is a cytokine involved in inflammation and activation of polymorphonuclear leukocytes. CCL3 has been detected in infiltrating cells and tumor cells. Chondrosarcoma is a highly malignant tumor that causes distant metastasis. However, the effect of CCL3 on human chondrosarcoma metastasis is still unknown. Here, we found that CCL3 increased cellular migration and expression of matrix metalloproteinase (MMP)-2 in human chondrosarcoma cells. Pre-treatment of cells with the MMP-2 inhibitor or transfection with MMP-2 specific siRNA abolished CCL3-induced cell migration. CCL3 has been reported to exert its effects through activation of its specific receptor, CC chemokine receptor 5 (CCR5). The CCR5 and AMP-activated protein kinase (AMPK) inhibitor or siRNA also attenuated CCL3-upregulated cell motility and MMP-2 expression. CCL3-induced expression of MMP-2 and migration were also inhibited by specific inhibitors, and inactive mutants of AMPK, p38 mitogen activated protein kinase (p38 or p38-MAPK), and nuclear factor κB (NF-κB) cascades. On the other hand, CCL3 treatment demonstrably activated AMPK, p38, and NF-κB signaling pathways. Furthermore, the expression levels of CCL3, CCR5, and MMP-2 were correlated in human chondrosarcoma specimens. Taken together, our results indicate that CCL3 enhances the migratory ability of human chondrosarcoma cells by increasing MMP-2 expression via the CCR5, AMPK, p38, and NF-κB pathways

A novel approach to sonographic examination in a patient with a calf muscle tear: a case report

© 2009 Chen et al; licensee Cases Network Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution Licens

Cyclooxygenase-2 enhances α2β1 integrin expression and cell migration via EP1 dependent signaling pathway in human chondrosarcoma cells

<p>Abstract</p> <p>Background</p> <p>Cyclooxygenase (COX)-2, the inducible isoform of prostaglandin (PG) synthase, has been implicated in tumor metastasis. Interaction of COX-2 with its specific EP receptors on the surface of cancer cells has been reported to induce cancer invasion. However, the effects of COX-2 on migration activity in human chondrosarcoma cells are mostly unknown. In this study, we examined whether COX-2 and EP interaction are involved in metastasis of human chondrosarcoma.</p> <p>Results</p> <p>We found that over-expression of COX-2 or exogenous PGE₂increased the migration of human chondrosarcoma cells. We also found that human chondrosarcoma tissues and chondrosarcoma cell lines had significant expression of the COX-2 which was higher than that in normal cartilage. By using pharmacological inhibitors or activators or genetic inhibition by the EP receptors, we discovered that the EP1 receptor but not other PGE receptors is involved in PGE₂-mediated cell migration and α2β1 integrin expression. Furthermore, we found that human chondrosarcoma tissues expressed a higher level of EP1 receptor than normal cartilage. PGE₂-mediated migration and integrin up-regulation were attenuated by phospholipase C (PLC), protein kinase C (PKC) and c-Src inhibitor. Activation of the PLCβ, PKCα, c-Src and NF-κB signaling pathway after PGE₂treatment was demonstrated, and PGE₂-induced expression of integrin and migration activity were inhibited by the specific inhibitor, siRNA and mutants of PLC, PKC, c-Src and NF-κB cascades.</p> <p>Conclusions</p> <p>Our results indicated that PGE₂enhances the migration of chondrosarcoma cells by increasing α2β1 integrin expression through the EP1/PLC/PKCα/c-Src/NF-κB signal transduction pathway.</p