Taxanes convert regions of perturbed microtubule growth into rescue sites

Microtubules are polymers of tubulin dimers, and conformational transitions in the microtubule lattice drive microtubule dynamic instability and affect various aspects of microtubule function. The exact nature of these transitions and their modulation by anti -cancer drugs such as Taxol and epothilone, which can stabilize microtubules but also perturb their growth, are poorly understood. Here, we directly visualize the action of fluorescent Taxol and epothilone derivatives and show that microtubules can transition to a state that triggers cooperative drug binding to form regions with altered lattice conformation. Such regions emerge at growing microtubule ends that are in a pre-catastrophe state and inhibit microtubule growth and shortening. Electron microscopy and in vitro dynamics data indicate that taxane accumulation zones represent incomplete tubes that can persist, incorporate tubulin dimers and repeatedly induce microtubule rescues. Thus, taxanes modulate the material properties of microtubules by converting destabilized growing microtubule ends into regions resistant to depolymerization

An overview on the reactors to study drinking water biofilms

The development of biofilms in drinking water distribution systems (DWDS) can cause pipe degradation, changes in the water organoleptic properties but the main problem is related to the public health. Biofilms are the main responsible for the microbial presence in drinking water (DW) and can be reservoirs for pathogens. Therefore, the understanding of the mechanisms underlying biofilm formation and behavior is of utmost importance in order to create effective control strategies. As the study of biofilms in real DWDS is difficult, several devices have been developed. These devices allow biofilm formation under controlled conditions of physical (flow velocity, shear stress, temperature, type of pipe material, etc), chemical (type and amount of nutrients, type of disinfectant and residuals, organic and inorganic particles, ions, etc) and biological (composition of microbial community e type of microorganism and characteristics) parameters, ensuring that the operational conditions are similar as possible to the DWDS conditions in order to achieve results that can be applied to the real scenarios. The devices used in DW biofilm studies can be divided essentially in two groups, those usually applied in situ and the bench top laboratorial reactors. The selection of a device should be obviously in accordance with the aim of the study and its advantages and limitations should be evaluated to obtain reproducible results that can be transposed into the reality of the DWDS. The aim of this review is to provide an overview on the main reactors used in DW biofilm studies, describing their characteristics and applications, taking into account their main advantages and limitations.This work was supported by the Operational Programme for Competitiveness Factors COMPETE and by Portuguese Foundation for Science and Technology through Project Phyto disinfectants - PTDC/DTPSAP/1078/2012 (COMPETE: FCOMP-01-0124-FEDER-028765), the Post-Doc grant awarded to Lucia Simoes (SFRH/BPD/81982/2011). Also, this work was undertaken as part of the European Research Project SUS-CLEAN (Contract n_FP7-KBBE-2011-5, project number: 287514) and the COST Action FA1202. The authors are solely responsible for this work. It does not represent the opinion of the Community, and the Community is not responsible for any use that might be made of data appearing herein

The action of chemical and mechanical stresses on single and dual species biofilm removal of drinking water bacteria

The presence of biofilms in drinking water distribution systems (DWDS) is a global public health concern as they can harbor pathogenic microorganisms. Sodium hypochlorite (NaOCl) is the most commonly used disinfectant for microbial growth control in DWDS. However, its effect on biofilm removal is still unclear. This work aims to evaluate the effects of the combination of chemical (NaOCl) and mechanical stresses on the removal of single and dual species biofilms of two bacteria isolated from DWDS and considered opportunistic, Acinectobacter calcoaceticus and Stenotrophomonas maltophilia. A rotating cylinder reactor was successfully used for the first time in drinking water biofilm studies with polyvinyl chloride as substratum. The single and dual species biofilms presented different characteristics in terms of metabolic activity, mass, density, thickness and content of proteins and polysaccharides. Their complete removal was not achieved even when a high NaOCl concentrations and an increasing series of shear stresses (from 2 to 23 Pa) were applied. In general, NaOCl pre-treatment did not improve the impact of mechanical stress on biofilm removal. Dual species biofilms were colonized mostly by S. maltophilia and were more susceptible to chemical and mechanical stresses than these single species. The most efficient treatment (93% biofilm removal) was the combination of NaOCl at 175 mg·l1 with mechanical stress against dual species biofilms. Of concern was the high tolerance of S. maltophilia to chemical and mechanical stresses in both single and dual species biofilms. The overall results demonstrate the inefficacy of NaOCl on biofilm removal even when combined with high shear stresses.(i) POCI-01-0145-FEDER-006939 (Laboratory for Process Engineering, Environment, Biotechnology and Energy – UID/EQU/00511/2013) funded by the European Regional Development Fund (ERDF), through COMPETE2020 - Programa Operacional Competitividade e Internacionalização (POCI) and by national funds, through FCT - Fundação para a Ciência e a Tecnologia. (ii) NORTE-01-0145-FEDER-000005 – LEPABE-2-ECO-INNOVATION, supported by North Portugal Regional Operational Programme (NORTE 2020), under the Portugal 2020 Partnership Agreement, through the European Regional Development Fund (ERDF). (iii) Grants attributed by Portuguese Foundation for Science and Technology – FCT – to Inês Gomes (SFRH/BD/103810/2014) and Lúcia Simões (SFRH/BPD/81982/2011).info:eu-repo/semantics/publishedVersio

China Engages Global Health Governance: Processes and Dilemmas

Using HIV/AIDS, Severe Acute Respiratory Syndrome (SARS), and avian influenza as case studies, this paper discusses the processes and dilemmas of China's participation in health governance, both at the domestic level and the global level. Globalization has eroded the boundary between public and private health and between domestic and global health governance. In addition, the SARS outbreak of 2002-2003 focused global attention on China's public health. As a rising power with the largest population on earth, China is expected by the international community to play a better and more active role in health management. Since the turn of this century, China has increasingly embraced multilateralism in health governance. This paper argues that China's multilateral cooperation is driven by both necessity and conscious design. International concerns about good governance and its aspiration to become a 'responsible' state have exerted a normative effect on China to change tack. Its interactions with United Nations agencies have triggered a learning process for China to securitize the spread of infectious diseases as a security threat. Conversely, China has utilized multilateralism to gain access to international resources and technical assistance. It is still a matter of debate whether China's cooperative engagement with global health governance can endure, because of the persistent problems of withholding information on disease outbreaks and because of its insistence on the Westphalian notion of sovereignty

Assessment of joint space narrowing with conventional standing antero-posterior radiographs: relief in mild-to-moderate pain is not a confounder in recent osteoarthritis structure-modifying drug trials

Objective: Knee pain relief has been suggested to potentially alter radioanatomic positioning in conventional standing antero-posterior knee radiographs. This study was performed to determine whether this is always the case and in particular if it applied to two recent randomised, placebo-controlled trials showing both symptom- and structure-modification with glucosamine sulfate in knee osteoarthritis. Design: Patients in the two studies were selected if they completed the 3-year evaluations and, irrespectively of treatment, (1) were pain-improvers in that they underwent Western Ontario and McMaster Universities (WOMAC) osteoarthritis index (WOMAC) pain decrease at least equal to the mean improvement observed with glucosamine sulfate, or (2) if their baseline standing knee pain (item #5 of the WOMAC pain scale) was "severe" or "extreme" and improved by any degree at the end of the trials. Changes in minimum joint space width were then compared between treatments. Results: Knee pain was of mild-to-moderate severity in the two original studies and in all patient subsets identified here. Obviously, there were more pain-improvers in the glucosamine sulfate than in the placebo subsets (N 76 vs 57 in pooling the two studies), but WOMAC pain scores improved to the same extent (over 50% relative to baseline). Notwithstanding such a major pain relief, patients in the placebo subsets of both studies suffered a definite mean (SE) joint space narrowing, that was of -0.22 (0.15) mm in the pooled analysis, and that was not observed with glucosamine sulfate: +0.15 (0.07) mm; P= 0.003. Similar evidence was found in the smaller subsets with at least severe baseline standing knee pain improving after 3 years. Conclusions: Knee pain relief did not bias the report of a structure-modifying effect of glucosamine sulfate in two recent long-term trials, possibly due to the mild-to-moderate patient characteristics. Consensus deliverables should acknowledge that the potential limitations of conventional standing antero-posterior radiographs should not be overestimated since they may not apply to all patient populations and to all studies using this gold standard technique. (C) 2006 OsteoArthritis Research Society International. Published by Elsevier Ltd. All rights reserved

Total Joint Replacement after Glucosamine Sulphate Treatment in Knee Osteoarthritis: Results of a Mean 8-Year Observation of Patients from Two Previous 3-Year, Randomised, Placebo-Controlled Trials

OBJECTIVE: To assess the incidence of Total Joint Replacement (TJR) during the long-term follow-up of patients with knee osteoarthritis (OA) formerly receiving treatment with glucosamine sulphate or placebo. METHODS: Knee OA patients participating in two previous randomised, placebo-controlled, double-blind, 3-year trials of glucosamine sulphate and receiving treatment for at least 12 months, were systematically contacted to participate in a long-term follow-up retrospective assessment of the incidence of total knee replacement. RESULTS: Out of 340 patients with at least 12 months of treatment, 275 (i.e., 81%) could be retrieved and interviewed for the present evaluation: 131 formerly on placebo and 144 on glucosamine sulphate. There were no differences in baseline disease characteristics between groups or with the patients lost to follow-up. The mean duration of follow-up was approximately 5 years after trial termination and treatment discontinuation, making up a total of 2178 patient-years of observation (including treatment and follow-up). Total knee replacement had occurred in over twice as many patients from the placebo group, 19/131 (14.5%), than in those formerly receiving glucosamine sulphate, 9/144 (6.3%) (P=0.024, chi-square test), with a Relative Risk that was therefore 0.43 (95% confidence interval (CI): 0.20-0.92), i.e., a 57% decrease compared with placebo. The Kaplan Meier/Log-Rank test survival analysis confirmed a significantly decreased (P=0.026) cumulative incidence of total knee replacements in patients who had received glucosamine sulphate. A pharmacoeconomic analysis in a subgroup of subjects suggested that patients formerly on glucosamine sulphate had recurred to less symptomatic medications and use of other health resources than those from the placebo group during the last year of follow-up. CONCLUSIONS: Treatment of knee OA with glucosamine sulphate for at least 12 months and up to 3 years may prevent TJR in an average follow-up of 5 years after drug discontinuation

Relief in mild-to-moderate pain is not a confounder in joint space narrowing assessment of full extension knee radiographs in recent osteoarthritis structure modifying drug trials

Objective: To assess whether improvement in knee pain biased the determination of the structure-modifying effect reported for glucosamine sulfate in two recent 3-year, randomised, placebo-controlled clinical trials, in which conventional standing antero-posterior full extension knee radiographs were used for the measurement of joint space narrowing, and in which pain relief might have improved knee full extension. Design: Patients completing the 3-year treatment course were selected based on a WOMAC pain decrease at least equal to the mean improvement in the glucosamine sulfate arms in either of the original studies, irrespective of treatment with glucosamine sulfate or placebo (drug responders or placebo responders). In a second approach, 3-year completers were selected if their baseline standing knee pain (item #5 of the WOMAC pain scale) was 'severe' or 'extreme' and improved by any degree at the end of the trials. In both cases, changes in minimum joint space width were compared between treatment groups. Results: Global knee pain was rnild-to-moderate in the two study populations and in all patient subsets identified. There were obviously more pain improvers in the glucosamine sulfate subsets (N=76 in the two studies combined) than in the placebo subsets (N=57), but WOMAC pain scores improved to the same extent, which was as large as over 50% relative to baseline. Nevertheless, the placebo subsets in both studies underwent an evident mean (SD) joint space narrowing, which in the pooled analysis of both studies was -0.22 (0.80) mm, and was not observed with glucosamine sulfate: +0.15 (0.60) mm (P=0.003 vs placebo). Similar results were found in the smaller subsets with greater than or equal to severe baseline standing knee pain that improved after 3 years, with a joint space narrowing nevertheless of -0.28 (0.76) mm with placebo (N=26), not observed with glucosamine sulfate: +0.21 (0.68) mm (N=31; P=0.014 vs placebo). Conclusions: Knee pain relief did not bias the report of a structure-modifying effect of glucosamine sulfate in two recent long-term trials using conventional standing antero-posterior radiographs, possibly due to the mild-to-moderate patient characteristics. (C) 2003 OsteoArthritis Research Society International. Published by Elsevier Ltd. All rights reserved