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Newer treatments of advanced human cancer are based on combination of cancer drugs that have different mechanism of actions yet the combination strategy may potentiate the anti-cancer effects and cytotoxicity. Recent studies suggest that cancer growth can be inhibited more effectively by combination of phytochemicals that affect different pathways. The apoptotic activity can be modulated by intrinsic and extrinsic molecules. The combination of anti-tumor phytochemicals can be more effective in modulating different signaling pathways associated with tumor cell growth which is the common target for anti-tumor action. Combinations of cytotoxic anti-tumor agents and inhibitors from phytochemicals are believed to act together producing inhibitory mechanisms on cancer growth. This combination strategy shows promise on cancer therapy. However, the combination of phytochemicals in cancer therapy needs to be further investigated to develop a better treatment strategy. Recent patents on anti-tumor phytochemicals are reviewed in this article.

Naturally occurring plant alkaloids, in particular those identified from herbal medicines, are finding therapeutic use. Heart diseases can be well managed with specific formulations of herbal medicines. The combined action of multiple constituents of herbal medicines works with therapeutic benefits in humans. The established formulations of Traditional Chinese medicines show efficacy in treatment of diseases. However, individual herbal principles seldom show pharmacological activity. Nevertheless, some of the active alkaloids and terpenoids from medicinal herbs have been identified. The pharmacological activities of these herbal compounds have been studied. These active constituents of herbal medicine are also used in nutrient supplements, but the modes of action of the active component remain sketchy. The present review describes the recent development of those active principles from herbal medicines as cardiovascular agents. The study will provide insights into herbal medicines for drug development for the treatment of cardiovascular disease.

Objective: To assess systemically with meta-analysis the trend of survival and its determinants, which are hindering further improvement of survival of patients with systemic lupus erythematosus (SLE) over the past 5 decades., Methods: Retrospective, cross-sectional, and prospective observational studies addressing survival and damage in SLE patients published between 1 January 1950 and 31 July 2010 were identified in electronic databases. Using the random-effects model, effect size was calculated based on the logit of the overall 5- and 10-year survival rates. The pooled logit and its robust 95% confidence interval were transformed back into the 5- and 10-year survival rates, after adjusting for potential dependence on the data. Potential factors predicting the pooled survival rates were explored by meta-regression., Results: Seventy-seven studies involving 18,998 SLE patients were analyzed. Between the 1950s and the 2000s, their overall survival significantly increased, from 74.8% to 94.8% and 63.2% to 91.4% for the overall 5-year and 10-year survival, respectively (P < 0.001). The survival improvement, however, appeared to slow down between 1980 and 1990. Meta-regression revealed that neuropsychiatric and renal damage negatively affected the overall 5-year survival, whereas neuropsychiatric damage remained so for the 10-year survival for the past 50 years. Furthermore, the prevalence of neuropsychiatric damage has been significantly increasing over the past 5 decades., Conclusions: For the past 50 years, damage involving the renal and neuropsychiatric systems has been negatively affecting survival of SLE patients. Early detection and aggressive management of renal and neuropsychiatric involvement may potentially improve further the survival of lupus patients., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Meta-analysis is a statistical method to compare and combine effect sizes from a pool of relevant empirical studies. It is now a standard approach to synthesize research findings in many disciplines, including medical and healthcare research. This paper is the third paper of a mini-series introducing systematic review and meta-analysis. First, common effect sizes used in meta-analysis are presented. Fixed-, random- and mixed-effects models are then introduced. Next, a real data set from a published meta-analysis will be used to illustrate the procedures and interpretations. Last, software packages that may be used to conduct meta-analyses will be highlighted., (© 2012 The Authors International Journal of Rheumatic Diseases © 2012 Asia Pacific League of Associations for Rheumatology and Blackwell Publishing Asia Pty Ltd.)

Objective: This meta-analysis was aimed to evaluate the differences in aggregated prevalence of depressive symptoms among people with chronic obstructive pulmonary disease (COPD) as compared to controls without COPD and to determine underlying moderators to explain potential heterogeneity of prevalence., Methods: A meta-analysis of published work was performed using the random effect model. A total of eight studies were identified. We calculated the differences in prevalence proportion of depressive symptoms in patients with COPD versus controls. Meta-regression and subgroup analysis were performed to identify factors that may contribute to heterogeneity., Results: The prevalence proportion of depressive symptoms was found to be significantly higher (pooled odds ratio: 2.81; 95% CI: 1.69-4.66) among 39587 individuals with COPD as compared to 39,431 controls (24.6%, 95% CI: 20.0-28.6% vs. 11.7%, 95% CI: 9-15.1%). Meta-regression was conducted to account for the heterogeneity of the prevalence proportion, but moderators like mean age, gender, mean FEV(1) and proportion of current smokers among COPD patients were nonsignificant and could not explain heterogeneity in prevalence of depressive symptoms. Subgroup analyses showed no significant differences based on different methods of assessment of depressive symptoms and countries sampled., Conclusion: This meta-analytical review identified higher prevalence of depressive symptoms among COPD patients, and meta-regression showed that demographic and clinical factors were not the determinants of heterogeneity in prevalence of depressive symptoms., (Copyright © 2011 Elsevier Inc. All rights reserved.)

Aim: Prompted by a clinical question, we critically appraised a meta-analysis of efficacy and safety of mycophenolate mofetil (MMF) versus cyclophosphamide (CYC) in the treatment of proliferative lupus nephritis., Methods: Systemic reviews and a meta-analysis are introduced to the reader in the perspective of a clinical scenario that raises questions about applicability of certain treatment options in clinical practice. Critical appraisal of meta-analysis addresses three questions. (i) What are the results? (ii) Are the results valid? (iii) How can I apply the results to my patient care?, Results: A meta-analysis paper titled 'Mycophenolate mofetil is as efficacious as, but safer than, cyclophosphamide in the treatment of proliferative lupus nephritis: a meta-analysis and meta-regression'by Mak et al. (2009) was selected. Our critical appraisal identified several strengths of the paper, such as having a clearly focused clinical question, considering clinically important outcomes, using appropriate inclusion criteria to select primary studies, assessing quality of selected papers, good reproducibility in the assessment of primary studies and performing sensitivity analysis and meta-regression to account for heterogeneity. Nevertheless, we also identified several weaknesses, such as possibly missing out other relevant studies, possible selection bias, low quality of some primary studies used and lack of data on cost effectiveness., Conclusion: Meta-analyses have an important role in the implementation of evidence-based practice and shaping of future research. Despite the undoubted advantages, meta-analyses are no panacea. Caution, therefore, has to be applied when using the results of meta-analyses in clinical practice, due to methodological limitations of the meta-analyses and limitations in the primary studies used.

Meta-analysis, a complex statistical method which involves synthesis of data from relevant studies to devise an effect size or a conclusion, has increasingly been recognized and impacts on evidence-based medicine, especially in the field of health science. Thanks to the advent and unmet need of evidence-based medicine, since the first recordable publication of a meta-analysis in 1904 addressing the effectiveness of typhoid vaccine, both the number and quality of meta-analyses published relating to healthcare science have been on a steep rise. If properly conducted, based on answering relevant clinical questions, strict selection criteria of participating studies, appropriate analytical methods, and proper presentation of results, coupled with critical and faithful discussion on the strength and weakness of the analysis, meta-analysis will definitely be an invaluable tool for clinicians and researchers in understanding epidemiology, justifying and refining hypotheses of various diseases, for medical practitioners to implement sound management decisions based on evidence-based medicine, and ultimately, for policy-makers to formulate cost-efficient treatment strategies, guidelines and legislation. In this first paper of a mini-series, the current trend of meta-analysis publications in the medical literature, examples of important meta-analyses relevant to rheumatology and the pros and cons of meta-analysis, will be discussed. Important terminology related to meta-analysis, the systematic ways to critically appraise, and finally the preferred methodology of conducting meta-analysis will be covered in the subsequent three reviews of this mini-series.

The presence of outliers and influential cases may affect the validity and robustness of the conclusions from a meta-analysis. While researchers generally agree that it is necessary to examine outlier and influential case diagnostics when conducting a meta-analysis, limited studies have addressed how to obtain such diagnostic measures in the context of a meta-analysis. The present paper extends standard diagnostic procedures developed for linear regression analyses to the meta-analytic fixed- and random/mixed-effects models. Three examples are used to illustrate the usefulness of these procedures in various research settings. Issues related to these diagnostic procedures in meta-analysis are also discussed. Copyright © 2010 John Wiley & Sons, Ltd., (Copyright © 2010 John Wiley & Sons, Ltd.)

Objective: The combination of heparin and aspirin was regarded as the 'standard therapy' for patients with recurrent pregnancy loss (RPL) and positive aPL antibodies to enhance live births, but it largely stems from expert opinion. We performed a meta-analysis of randomized controlled trials (RCTs) to assess whether this combination works better than aspirin alone., Methods: RCTs testing the efficacy of a combination of heparin and aspirin vs aspirin alone in patients with RPL and positive aPL antibodies were identified in electronic databases. Random effect meta-analysis was employed to pool relative risks (RRs) (with 95% CI) of live births as the primary outcome. RRs of obstetrical complications and standardized mean difference of birth weight were the secondary outcomes. Mixed-effects meta-regression was performed to identify factors associated with live births., Results: Data from five trials involving 334 patients were analysed. The overall live birth rates were 74.27 and 55.83% in the combination and aspirin alone groups, respectively. Patients who received heparin and aspirin had significantly higher live birth rate (RR 1.301; 95% CI 1.040, 1.629) than aspirin alone, with the number needed to achieve one live birth being 5.6. No significant differences in pre-eclampsia, preterm labour and birth weight were found between both the groups. Meta-regression using age at randomization, previous history of live births and episodes of miscarriages as covariates failed to predict the RR of live birth., Conclusions: The combination of heparin and aspirin is superior to aspirin alone in achieving more live births in patients with positive aPL antibodies and RPL.

Background: Occurrence of atrial fibrillation (AF) amongst bisphosphonate users has been increasingly reported but results are conflicting. We performed a Bayesian meta-analysis to address the possible association between the occurrence of AF and bisphosphonate use and estimated the posterior probability of development of AF with bisphosphonate use., Methods: Randomized controlled trials (RCTs) evaluating the efficacy and safety of bisphosphonates for treating and preventing osteoporosis, and observational studies investigating the incidence of AF amongst bisphosphonate users, were searched in electronic databases. We pooled the effect size with Bayesian meta-analysis for odds ratio (OR) and calculated its posterior probability of development of AF in bisphosphonate users for RCTs and observational studies, reported with the 95% credible interval (CI)., Results: Of 1751 potentially relevant citations initially retrieved, 4 RCTs and 2 reports of RCTs, and 3 observational studies were included for this meta-analysis. On pooling the RCTs, there was a non-significantly higher risk of overall (OR 1.184, 95% CI 0.837-1.656) and serious AF (OR 1.590, 95% CI 0.613-3.751) in bisphosphonate-treated patients. Combining data of observational studies also revealed a non-significantly higher risk of AF in bisphosphonate users (OR 1.251, 95% CI 0.980-1.732). Using Bayesian meta-analysis based on the effect size of observational studies as the prior, the posterior probability of OR>1.2 in the development of AF amongst bisphosphonate users in the RCTs was 0.484. Egger's regression demonstrated no notable publication bias in all the analyses., Conclusion: The current meta-analysis revealed no evidence of a higher risk of AF associated with bisphosphonate use. Nevertheless, based on Bayesian meta-analysis with the effect size of the observational studies as the prior, the posterior probabilities of development of AF was found to be 0.484 if the risk of AF was estimated to be more than 20%. The results of the current meta-analysis thus offer clinicians the practical probability of development of AF in patients who take bisphosphonates for the treatment of bone loss and corticosteroid induced osteoporosis.

Mediation models are often used as a means to explain the psychological mechanisms between an independent and a dependent variable in the behavioral and social sciences. A major limitation of the unstandardized indirect effect calculated from raw scores is that it cannot be interpreted as an effect-size measure. In contrast, the standardized indirect effect calculated from standardized scores can be a good candidate as a measure of effect size because it is scale invariant. In the present article, 11 methods for constructing the confidence intervals (CIs) of the standardized indirect effects were evaluated via a computer simulation. These included six Wald CIs, three bootstrap CIs, one likelihood-based CI, and the PRODCLIN CI. The results consistently showed that the percentile bootstrap, the bias-corrected bootstrap, and the likelihood-based approaches had the best coverage probability. Mplus, LISREL, and Mx syntax were included to facilitate the use of these preferred methods in applied settings. Future issues on the use of the standardized indirect effects are discussed.

Meta-analysis and structural equation modeling (SEM) are two important statistical methods in the behavioral, social, and medical sciences. They are generally treated as two unrelated topics in the literature. The present article proposes a model to integrate fixed-, random-, and mixed-effects meta-analyses into the SEM framework. By applying an appropriate transformation on the data, studies in a meta-analysis can be analyzed as subjects in a structural equation model. This article also highlights some practical benefits of using the SEM approach to conduct a meta-analysis. Specifically, the SEM-based meta-analysis can be used to handle missing covariates, to quantify the heterogeneity of effect sizes, and to address the heterogeneity of effect sizes with mixture models. Examples are used to illustrate the equivalence between the conventional meta-analysis and the SEM-based meta-analysis. Future directions on and issues related to the SEM-based meta-analysis are discussed., (Copyright (c) 2008 APA, all rights reserved.)

Health education can offer a valuable window onto conceptual and behavioral change. In Study 1, we mapped out 3rd-grade Chinese children's beliefs about causes of colds and flu and ways they can be prevented. We also explored older adults' beliefs as a possible source of the children's ideas. In Study 2, we gave 3rd- and 4th-grade Chinese children either a conventional cold/flu education program or an experimental "Think Biology" program that focused on a biological causal mechanism for cold/flu transmission. The "Think Biology" program led children to reason about cold/flu causation and prevention more scientifically than the conventional program, and their reasoning abilities dovetailed with their mastery of the causal mechanism. Study 3, a modified replication of Study 2, found useful behavioral change as well as conceptual change among children who received the "Think Biology" program and documented coherence among knowledge enrichment, conceptual change, and behavioral change.

Lipoprotein metabolism plays an important role in the development of several human diseases, including coronary artery disease and the metabolic syndrome. A good comprehension of the factors that regulate the metabolism of the various lipoproteins is therefore key to better understanding the variables associated with the development of these diseases. Among the players identified are regulators such as caveolins and caveolae. Caveolae are small plasma membrane invaginations that are observed in terminally differentiated cells. Their most important protein marker, caveolin-1, has been shown to play a key role in the regulation of several cellular signaling pathways and in the regulation of plasma lipoprotein metabolism. In the present paper, we have examined the role of caveolin-1 in lipoprotein metabolism using caveolin-1-deficient (Cav-1(-/-)) mice. Our data show that, while Cav-1(-/-) mice show increased plasma triglyceride levels, they also display reduced hepatic very low-density lipoprotein (VLDL) secretion. Additionally, we also found that a caveolin-1 deficiency is associated with an increase in high-density lipoprotein (HDL), and these HDL particles are enriched in cholesteryl ester in Cav-1(-/-) mice when compared with HDL obtained from wild-type mice. Finally, our data suggest that a caveolin-1 deficiency prevents the transcytosis of LDL across endothelial cells, and therefore, that caveolin-1 may be implicated in the regulation of plasma LDL levels. Taken together, our studies suggest that caveolin-1 plays an important role in the regulation of lipoprotein metabolism by controlling their plasma levels as well as their lipid composition. Thus caveolin-1 may also play an important role in the development of atherosclerosis.

There have been several studies in Western societies on the causes and consequences of sexual satisfaction within marriage. Little is known, however about the marital sexual relationship in Chinese societies. Moreover, most published studies used married individuals rather than married couples as participants. The present study examined data from a well-established knowledge, attitude, and practice (KAP) survey of 1,124 Hong Kong Chinese couples on martial sexual relationship. A conceptual model was tested using structural equation modeling (SEM). Interest in sex was found to be the strongest predictor of both sexual satisfaction and frequency of sex for both husbands and wives. Among the sociodemographic variables, the following two were significantly associated with lower frequencies of sex: for wives, that of having a full-time job; and for husbands, the factor of age. Theoretical implications for research on the interplay among culture, marriage, and sex in non-Western societies are discussed.

Features of posttraumatic stress disorder (PTSD) for 596 survivors of motor vehicle accidents were examined by self-report measures at 1 week, 1 month, 3 months, and 6 months after the motor vehicle accident (MVA). Latent growth modeling was utilized to study the trend and predictors of the level of distress. Results indicated that 5-20% of the participants reported to have a significant level of posttraumatic stress in one, two, or three of the PTSD symptom clusters within the period studied. Survivors with significant acute stress 1 week after the MVA had a higher risk for developing chronic posttraumatic stress. Although the severity of intrusive and hyperarousal symptoms decreased over time, the severity of avoidance symptoms remained unchanged. Factors predicting the course of PTSD after an MVA are identified.

Caveolae are 50- to 100-nm cell surface plasma membrane invaginations present in terminally differentiated cells. They are characterized by the presence of caveolin-1, sphingolipids, and cholesterol. Caveolin-1 is thought to play an important role in the regulation of cellular cholesterol homeostasis, a process that needs to be properly controlled to limit and prevent cholesterol accumulation and eventually atherosclerosis. We have recently generated caveolin-1-deficient [Cav-1(-/-)] mice in which caveolae organelles are completely eliminated from all cell types, except cardiac and skeletal muscle. In the present study, we examined the metabolism of cholesterol in wild-type (WT) and Cav-1(-/-) mouse embryonic fibroblasts (MEFs) and mouse peritoneal macrophages (MPMs). We observed that Cav-1(-/-) MEFs are enriched in esterified cholesterol but depleted of free cholesterol compared with their wild-type counterparts. Similarly, Cav-1(-/-) MPMs also contained less free cholesterol and were enriched in esterified cholesterol on cholesterol loading. In agreement with this finding, caveolin-1 deficiency was associated with reduced free cholesterol synthesis but increased acyl-CoA:cholesterol acyl-transferase (ACAT) activity. In wild-type MPMs, we observed that caveolin-1 was markedly upregulated on cholesterol loading. Despite these differences, cellular cholesterol efflux from MEFs and MPMs to HDL was not affected in the Cav-1-deficient cells. Neither ATP-binding cassette transporter G1 (ABCG1)- nor scavenger receptor class B type I (SR-BI)-mediated cholesterol efflux was affected. Cellular cholesterol efflux to apolipoprotein A-I was not significantly reduced in Cav-1(-/-) MPMs compared with wild-type MPMs. However, ABCA1-mediated cholesterol efflux was clearly more sensitive to the inhibitory effects of glyburide in Cav-1(-/-) MPMs versus WT MPMs. Taken together, these findings suggest that caveolin-1 plays an important role in the regulation of intracellular cholesterol homeostasis and can modulate the activity of other proteins that are involved in the regulation of intracellular cholesterol homeostasis.

Silver nanodendrites are synthesized by a simple surfactant-free method using a suspension of zinc microparticles as a heterogeneous reducing agent. Structural characterizations suggest the preferential growth along 100 and 111 directions by oriented attachment of silver nanocrystals in the diffusion limit, leading to the formation of silver nanodendrites 20-30 nm in stem and branch diameter and 5-50 microm in length. Surface-enhanced Raman scattering studies show that the silver nanodentrites give an intensive and enhanced Raman scattering when pyridine was used as a probing molecule. We have also demonstrated that the silver nanodendrites increase the sensitivity of an electrochemical glucose biosensor by as much as 1-2 orders of magnitude.

This study investigates how individuals formulate flexible coping strategies across situations by proposing differentiation and integration as two stress-appraisal processes. Results showed that participants who coped more flexibly adopted the dimensions of controllability and impact in differentiating among different stressful situations. They also deployed an integrated strategy: the deployment of more monitoring in situations perceived as controllable but less of this strategy in situations perceived as uncontrollable. Participants who coped less flexibly did not adopt any given dimensions and tended to use more monitoring regardless of situational characteristics. These results suggest that individuals with different extents of coping flexibility differ in the cognitive processes. Individuals who cope more flexibly display a greater extent of differentiation and integration than do those who cope less flexibly. These findings are translated into strategies for stress management workshops.

To synthesize studies that use structural equation modeling (SEM), researchers usually use Pearson correlations (univariate r), Fisher z scores (univariate z), or generalized least squares (GLS) to combine the correlation matrices. The pooled correlation matrix is then analyzed by the use of SEM. Questionable inferences may occur for these ad hoc procedures. A 2-stage structural equation modeling (TSSEM) method is proposed to incorporate meta-analytic techniques and SEM into a unified framework. Simulation results reveal that the univariate-r, univariate-z, and TSSEM methods perform well in testing the homogeneity of correlation matrices and estimating the pooled correlation matrix. When fitting SEM, only TSSEM works well. The GLS method performed poorly in small to medium samples., (Copyright 2005 APA, all rights reserved.)

It is generally well accepted that caveolin-3 expression is muscle specific, whereas caveolin-1 and -2 are coexpressed in a variety of cell types, including adipocytes, endothelial cells, epithelial cells, and fibroblasts. Caveolin-1 and -2 are known to form functional hetero-oligomeric complexes in cells where they are coexpressed, whereas caveolin-3 forms homo-oligomeric high molecular mass complexes. Although caveolin-2 might be expected to interact in a similar manner with caveolin-3, most studies indicate that this is not the case. However, this view has recently been challenged as it has been demonstrated that caveolin-2 and -3 are coexpressed in primary cultures of cardiac myocytes, where these two proteins can be coimmunoprecipitated. Thus it remains controversial whether caveolin-2 interacts with caveolin-3. Here, we directly address the issue of caveolin isoform protein-protein interactions by means of three distinct molecular genetic approaches. First, using caveolin-1-deficient mouse embryonic fibroblasts, in which we have stably expressed caveolin-1, -2, or -3, we find that caveolin-1 interacts with caveolin-2 in this setting, whereas caveolin-3 does not, in agreement with most published observations. Next, we used a transfected L6 myoblast cell system expressing all three caveolin proteins. Surprisingly, we found that caveolin-1, -2, and -3 all coimmunoprecipitate in this cell type, suggesting that this interaction is muscle cell specific. Similar results were obtained when the skeletal muscle of caveolin-1 transgenic animals was analyzed for caveolin-1 and caveolin-3 coimmunoprecipitation. Thus we conclude that all three caveolins can interact to form a discrete hetero-oligomeric complex, but that such complex formation is clearly muscle specific.

This study examined anxiety and coping responses to the outbreak of severe acute respiratory syndrome (SARS) in Hong Kong. Trait anxiety, situation-specific coping strategies, and coping flexibility were proposed as predictors of state anxiety during the early phase of the SARS epidemic. Seventy-two Hong Kong undergraduates (31 men, 41 women) participated in a prospective, multiple time-point study. Participants' trait anxiety and coping flexibility had been assessed in an earlier study. Five months later, they reported their anxiety and coping at each of the four time points during the outbreak. Results revealed fluctuations in state anxiety across time points. Results from hierarchical linear modeling showed that trait anxiety as well as the situation-appropriate coping strategies of avoidance and personal hygiene practice accounted for changes in state anxiety.

Objectives: Pulmonary hypertension (PH) and lung structural remodeling are frequent complications of congestive heart failure (CHF). Yet, the molecular mechanisms involved in CHF-induced PH and lung remodeling remain unknown. Caveolins (Cav-1, -2 and -3) are the principal structural proteins of the vesicular invaginations of the plasma membrane, termed caveolae. Mice with homozygous deletion of the caveolin-1 gene (Cav-1(-/-)) have been shown to develop dilated cardiomyopathy, PH and lung structural remodeling, characterized by hypercellularity and thickening of the alveolar septa. However, the physiological relevance of these observations for the pathogenesis of PH and lung remodeling remains to be determined., Methods and Results: Here, we investigate the natural behavior of the endogenous caveolin proteins during the development of PH and lung structural remodeling, using a rat model of myocardial infarction (MI). MI was induced in male Wistar rats by ligating the left anterior coronary artery. Two weeks post-MI, rats were anesthetized and hemodynamic and morphometric measurements were obtained. Rats subjected to MI developed marked PH, lung structural remodeling and right ventricular hypertrophy (RVH). Both immunoblot analysis and immunohistochemistry dramatically show that Cav-1 and Cav-2 expression is downregulated to almost undetectable levels in the lungs of post-MI rats. Mechanistically, the reduced expression of caveolins was associated with the increased tyrosine-phosphorylation of the signal transducer and activator of transcription-3 (STAT3) and the upregulation of cyclin D1 and D3 expression. We also show that STAT3 is hyperphosphorylated, and cyclin D1 and D3 levels are dramatically upregulated, in lung tissue samples derived from Cav-1 (-/-)- and Cav-2 (-/-)-deficient mice., Conclusions: Thus, down-modulation of pulmonary Cav-1 and Cav-2 expression in rats subjected to MI may represent an initiating mechanism leading to the activation of the STAT3/Cyclins pathway and, ultimately, to the development of PH and lung structural remodeling.

Tumorigenesis is a multistep process that involves a series of genetic changes or "multiple hits," leading to alterations in signaling, proliferation, immortalization, and transformation. Many of the molecular factors that govern tumor initiation and progression remain unknown. Here, we evaluate the transformation suppressor potential of caveolin-1 (Cav-1) and its ability to cooperate with a well established tumor suppressor, the INK4a locus. To study the effects of loss of caveolin-1 on cellular transformation, we established immortalized primary mouse embryonic fibroblasts (MEFs) expressing and lacking caveolin-1 by interbreeding Cav-1 (+/+) and Cav-1 (-/-) mice with INK4a (-/-) mice. Analysis of these cells reveals that loss of caveolin-1 confers a significant growth advantage, as measured via cellular proliferation and cell cycle analysis. Loss of caveolin-1 in the INK4a (-/-) genetic background results in constitutive hyperactivation of the p42/44 MAP kinase cascade, decreased expression of p21(Cip1), as well as cyclin D1 and PCNA overexpression, consistent with their hyperproliferative phenotype. Importantly, in cells lacking Cav-1 expression, transformation by activated oncogenes (H-Ras(G12V) or v-Src) results in increased tumor growth in vivo (up to >40-fold). Finally, INK4a (-/-)/Cav-1 (-/-) mice demonstrate disturbed mammary epithelial ductal morphology, with hyperplasia, increased side-branching, and fibrosis. Our results provide important new evidence for the transformation suppressor properties of Cav-1 and the first molecular genetic evidence that Cav-1 cooperates with a tumor suppressor, namely the INK4a genetic locus.

Purpose: Caveolae are flask-shaped invaginations of the plasma membrane formed by the oligomerization of caveolins. Because only smooth muscle contains all caveolin (Cav) family members (Cav-1, 2 and 3), we examined the contribution of each caveolin to urogenital smooth muscle structure/function., Materials and Methods: WT, Cav-1, 2, 3 and -1/3 knockout (KO) mouse bladders were characterized by Western blot, co-immunoprecipitation, immunofluorescence microscopy, electron microscopy, histochemistry and pharmacological techniques. Cystometric analysis was performed in conscious, freely moving mice. Other urogenital organs were investigated by histological analysis., Results: The loss of bladder Cav-1 results in a marked decrease in Cav-2 but not Cav-3 expression. Ablation of Cav-3 fails to alter Cav-1 or Cav-2 expression. Deletion of Cav-1 results in the almost complete loss of caveolae, while Cav-2 KO and Cav-3 KO mouse smooth muscle showed a normal number of caveolae. The loss of Cav-1 generated caveolae led to significant urogenital changes in male mice (most marked by 12 months of age), namely 1) bladder weight-to-body weight ratios were increased, 2) the bladder smooth muscle layer was thickened, 3) the bladders had increased baseline, threshold and spontaneous pressures, 4) bladder strips showed a decreased contractile response to carbachol and KCl, and 5) these smooth muscle changes were accompanied by marked fluid accumulation in the prostate and seminal vesicles, with intracellular vacuolization in the kidneys. As such, male Cav-1 KO mice may be a useful animal model for studying LUTD (lower urinary tract dysfunction) that is so prevalent in aging male patients., Conclusions: The loss of Cav-1 and, thus, of most smooth muscle cell caveolae results in significant bladder dysfunction and urogenital organ changes in aged male mice.

Caveolin-1 is the principal structural component of caveolae microdomains, which represent a subcompartment of the plasma membrane. Several independent lines of evidence support the notion that caveolin-1 functions as a suppressor of cell transformation. For example, the human CAV-1 gene maps to a suspected tumor suppressor locus (D7S522/7q31.1) that is frequently deleted in a number of carcinomas, including breast cancers. In addition, up to 16% of human breast cancers harbor a dominant-negative mutation, P132L, in the CAV-1 gene. Despite these genetic associations, the tumor suppressor role of caveolin-1 still remains controversial. To directly assess the in vivo transformation suppressor activity of the caveolin-1 gene, we interbred Cav-1 (-/-) null mice with tumor-prone transgenic mice (MMTV-PyMT) that normally develop multifocal dysplastic lesions throughout the entire mammary tree. Herein, we show that loss of caveolin-1 gene expression dramatically accelerates the development of these multifocal dysplastic mammary lesions. At 3 wk of age, loss of caveolin-1 resulted in an approximately twofold increase in the number of lesions (foci per gland; 3.3 +/- 1.0 vs. 7.0 +/- 1.2) and an approximately five- to sixfold increase in the total area occupied by these lesions. Similar results were obtained at 4 wk of age. However, complete loss of caveolin-1 was required to accelerate the appearance of these dysplastic mammary lesions, because Cav-1 (+/-) heterozygous mice did not show any increases in foci development. We also show that loss of caveolin-1 increases the extent and the histological grade of these mammary lesions and facilitates the development of papillary projections in the mammary ducts. Finally, we demonstrate that cyclin D1 expression levels are dramatically elevated in Cav-1 (-/-) null mammary lesions, consistent with the accelerated appearance and growth of these dysplastic foci. This is the first in vivo demonstration that caveolin-1 can function as a transformation suppressor gene.

A growing body of evidence suggests that muscle cell caveolae may function as specialized membrane micro-domains in which the dystrophin-glycoprotein complex and cellular signaling molecules reside. Caveolin-3 (Cav-3) is the only caveolin family member expressed in striated muscle cell types (cardiac and skeletal). Interestingly, skeletal muscle fibers from Cav-3 (-/-) knock-out mice show a number of myopathic changes, consistent with a mild-to-moderate muscular dystrophy phenotype. However, it remains unknown whether a loss of Cav-3 affects the phenotypic behavior cardiac myocytes in vivo. Here, we present a detailed characterization of the hearts of Cav-3 knock-out mice. We show that these mice develop a progressive cardiomyopathic phenotype. At four months of age, Cav-3 knock-out hearts display significant hypertrophy, dilation, and reduced fractional shortening, as revealed by gated cardiac MRI and transthoracic echocardiography. Histological analysis reveals marked cardiac myocyte hypertrophy, with accompanying cellular infiltrates and progressive interstitial/peri-vascular fibrosis. Interestingly, loss of Cav-3 expression in the heart does not change the expression or the membrane association of the dystrophin-glycoprotein (DG) complex. However, a marker of the DG complex, alpha-sarcoglycan, was specifically excluded from lipid raft domains in the absence of Cav-3. Because activation of the Ras-p42/44 MAPK pathway in cardiac myocytes can drive cardiac hypertrophy, we next assessed the activation state of this pathway using a phospho-specific antibody probe. We show that p42/44 MAPK (ERK1/2) is hyperactivated in hearts derived from Cav-3 knock-out mice. These results are consistent with previous in vitro data demonstrating that caveolins may function as negative regulators of the p42/44 MAPK cascade. Taken together, our data argue that loss of Cav-3 expression is sufficient to induce a molecular program leading to cardiac myocyte hypertrophy and cardiomyopathy.

A multiresidue method is reported for the determination of atrazine and its dealkylated chlorotriazine metabolites in water. Water samples are buffered to pH 10 and partitioned in ethyl acetate. Final analysis is accomplished using gas chromatography/mass selective detection (GC/MSD) in the selected ion monitoring (SIM) mode. The limit of detection (LOD) is 0.050 ng and the limit of quantification (LOQ) is 0.10 ppb for 2-chloro-4-(ethylamino)-6-(isopropylamino)-s-triazine (atrazine), 2-amino-4-chloro-6-(isopropylamino)-s-triazine (G-30033), 2-amino-4-chloro-6-(ethylamino)-s-triazine (G-28279), and 2, 4-diamino-6-chloro-s-triazine (G-28273). The mean procedural recoveries were 90, 92, 98, and 85% and the standard deviations were 12, 13, 16, and 20% for atrazine, G-30033, G-28279, and G-28273, respectively (n = 30). The study was conducted under U.S. EPA FIFRA Good Laboratory Practice Guidelines 40 CFR 160 for method validation. The reported procedure accounts for residues of G-28273 in water that are not included in EPA Method 507.

An analytical method was developed for the determination in urine of 2 metabolites of diazinon: 6-methyl-2-(1-methylethyl)-4(1H)-pyrimidinone (G-27550) and 2-(1-hydroxy-1-methylethyl)-6-methyl-4(1H)-pyrimidinone (GS-31144). Two of the urine sample preparation procedures presented rely on gas chromatography/mass selective detection (GC/MSD) in the selected ion monitoring mode for determination of G-27550. For fast sample preparation and a limit of quantitation (LOQ) of 1.0 ppb, urine samples were purified by using ENV+ solid-phase extraction (SPE) columns. For analyte confirmation at an LOQ of 0.50 ppb, classical liquid/liquid partitioning was used before further purification in a silica SPE column. An SPE sample preparation procedure and liquid chromatography/electrospray ionization/mass spectrometry/mass spectrometry (LC/ESI/MS/MS) were used for both G-27550 and GS-31144. The limit of detection was 0.01 ng for G-27550 with GC/MSD, and 0.016 ng when LC/ESI/MS/MS was used for both G-27550 and GS-31144. The LOQ was 0.50 ppb for G-27550 when GC/MSD and the partitioning/SPE sample preparation procedure were used, and 1.0 ppb for the SPE only sample preparation procedure. The LOQ was 1.0 ppb for both analytes when LC/ESI/MS/MS was used.

A method is reported for the determination of cyromazine and melamine residues in soil. Soil samples are extracted twice via mechanical shaking, each time with 70% acetonitrile/30% 0.050 M ammomium carbonate for 30 min. An aliquot portion of the pooled extracts is subjected to strong cation exchange (SCX) purification on AG 50W-X4 resin. Final analysis is accomplished using liquid chromatography-ultraviolet (LC-UV) detection at a wavelength of 214 nm. Confirmatory analyses can be performed using gas chromatography-mass selective detection (GC-MSD) in the selected ion monitoring (SIM) mode. The limit of detection (LOD) is 2.5 ng injected and the limit of quantification (LOQ) is 10 ppb when using LC-UV for the analysis of N-cyclopropyl-1,3,5-triazine-2,4, 6-triamine (cyromazine) and 1,3,5-triazine-2,4,6-triamine (melamine). The LOD is 0.050 ng injected and the LOQ is 10 ppb when using GC-MSD for confirmatory analyses. The mean procedural recoveries were 97 and 95% and the standard deviations were 16 and 11% for cyromazine and melamine, respectively (n = 24), when using LC-UV. The mean procedural recoveries were 107 and 92% and the standard deviations were 9.9 and 16% for cyromazine and melamine, respectively (n = 29), when using GC-MSD. The method validation study was conducted under U.S. EPA FIFRA Good Laboratory Practice Guidelines 40 CFR 160. The method also passed an Independent Laboratory Validation (ILV) as per U.S. EPA FIFRA Subdivision N.

The effects of heavy metals, at sub-lethal concentrations, on activated sludge microbial ecosystem were investigated. Adsorption capacity and rate of copper, chromium, lead and zinc on microbial flocs were much faster than that of organic matters. Metals affected not only the adsorption rate of organic matters but also the COD adsorption capacity of the activated sludge. Effects of heavy metals, on wastewater treatment performance of a sequencing batch reactor were also studied. Metal-laden wastewater at sub-lethal levels affected the performance to different extents, depending on the hydraulic retention time. Metal ions acted as a strong competitor against the organic compounds for active sites on the bioflocs instead of acting as a toxic microbial inhibitor, thus hampering organic adsorption and affecting the COD removal efficiency under shorter HRTs.

A multiresidue method is reported for the determination of atrazine and its chloro dealkylated metabolites in urine. Urine samples were subjected to a protein precipitation procedure followed by further purification using strong anion exchange and silica solid-phase extraction columns. Final analysis was accomplished using gas chromatography/mass selective detection in the selected ion monitoring mode. The limits of detection were 0.050 ng injected for 2,4-diamino-6-chloro-s-triazine (G-28273) and 0.025 ng injected for 2-chloro-4-(ethylamino)-6-(isopropylamino)-s-triazine (atrazine), 2-amino-4-chloro-6-(isopropylamino)-s-triazine (G-30033), and 2-amino-4-chloro-6-(ethylamino)-s-triazine (G-28279). The limits of quantification were 1.0 ppb for atrazine and G-30033 and 2.0 ppb for G-28279 and G-28273. The mean procedural recoveries obtained during the method validation were 115, 113, 112, and 97% and the standard deviations were 10.6, 10.2, 9.5, and 16.1% for atrazine, G-30033, G-28279, and G-28273, respectively. Additional recovery data were obtained during a worker exposure study and during an outside ruggedness trial. All studies were conducted under U.S. EPA FIFRA Good Laboratory Practice Standards 40 CFR 160.

At the present time, a patient with a pacemaker who undergoes an anesthesia for a surgical procedure is very common, but a parturient with a permanent pacemaker scheduled for elective cesarean section (c/s) is very rare. Complete heart block in pregnancy is not a common event and it may be congenital or acquired, particularly secondary to cardiac surgery. In normal women, the heart rate is physiologically increased commensurate with need, whereas in a parturient with installment of an implanted fixed rate pacemaker of VVI mode her heart rate cannot accelerate to cope with increased physiological demand because of the fixed pacing rate. For cesarean section, because of destabilized cardiovascular adaptation, an anesthesiologist must focus on detecting the early signs of compromised cardiac output in order to avoid maternal as well as fetal distress. He may run considerable risk to administer general or regional anesthesia to this kind of parturient. We present a case report in managing the parturient installed a with non-rate response type pacemaker undergoing C/S under epidural anesthesia.

Bulking and foaming in activated sludge have been associated with filamentous overgrowth. Filamentous Nocardia amarae and nonfilamentous Pseudomonas auruginosa were cultured using fatty acids (C2-C24) as the sole carbon. N. amarae could utilize all acids tested for growth, whereas P. auruginosa hardly grew on acids with 12 or more carbons. Maximum specific growth rate and saturation constant of N. amarae on C24, at 0.048 h-1 and 1.520 g COD/L, respectively, were much lower than that of P. auruginosa, showing that N. amarae had a relatively stronger affinity for long-chain fatty acids. N. amarae was competitive in activated sludge processes that receive sewage containing a high proportion of long-chain fatty acids, oils, and fats.

The usefulness of the Widal test in diagnosing childhood typhoid fever in endemic areas was investigated. The test was done on 150 children with other febrile illnesses and 98 bacteriologically proved cases of typhoid fever. Of the 150 children with nontyphoidal fever, only one had an H agglutinin titer of 1:50. Using an H or O agglutinin titer of 1:50 or more as a criterion for diagnosis, a positive Widal test was found in 88% of typhoid fever cases on the first occasion on which the test was done. If the test was repeated at least 94% of the typhoid cases had a significant result. The Widal test is a useful diagnostic test in children in endemic areas, provided interpretation of the test is made against background information relating to agglutinin levels in normal children in the region.