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Trija Vaidya,1 Véronique Thomas-Ollivier,2 François Hug,2,3 Alain Bernady,4 Camille Le Blanc,5 Claire de Bisschop,1 Arnaud Chambellan2,6 1Laboratory MOVE (EA6314), Université de Poitiers, Faculty of Sport Sciences, Poitiers, France; 2Faculty of Sport Sciences, Movement–Interactions–Performance, MIP, EA 4334, Université de Nantes, Nantes F-4000, France; 3Institut Universitaire de France (IUF), Paris, France; 4Toki-Eder Centre Médical Cardio-Respiratoire, Cambo-Les-Bains, France; 5Physical Medicine and Rehabilitation Department, University Hospital of Nantes, Nantes, France; 6L’institut du Thorax, Laboratory MIP, UNIV Nantes, University Hospital of Nantes, Nantes, FranceCorrespondence: Arnaud ChambellanExplorations fonctionnelles, l’institut du thorax, CHU de Nantes, Bd Jacques Monod, Nantes Cedex 1 44093, FranceTel +33 240 165 511Fax +33 240 165 391Email arnaud.chambellan@chu-nantes.frIntroduction: The recently developed daily and clinical visit PROactive physical activity in COPD (PPAC) instruments are hybrid tools to objectively quantify the level of physical activity and the difficulties experienced in everyday life. Our aim was to translate these instruments for the French-speaking chronic obstructive pulmonary disease (COPD) community worldwide and evaluate the influence of weather and pollution on difficulty score.Methods: The translation procedure was conducted following the guidelines for cross-cultural adaptation process. The translated clinical visit (C-PPAC) was tested among COPD patients in France. A retest was conducted after an interval of at least 2 weeks. The C-PPAC difficulty score was then tested to see how sensitive it was to the influence of weather and outdoor pollution.Results: One hundred and seventeen COPD patients (age 65± 9 years; FEV1: 51± 20%) from 9 regions in France were included. The French version of C-PPAC was found comprehensible by the patients with an average score of 4.8/5 on a Likert-scale. It showed good internal consistency with Cronbach’s α> 0.90 and a good test retest reliability with an intraclass correlation coefficient of ≥ 0.80. The difficulty score was negatively correlated with duration of daylight (ρ=− 0.266; p< 0.01) and influenced by the intensity of rainfall (light vs. heavy rainfall: 68± 16 vs. 76± 14 respectively, p=0.045). The score was lower in patients receiving long term oxygen therapy (60± 15 vs. 71± 15, p< 0.01), but not correlated with the pollution indices.Conclusion: The French versions of the questionnaires of the PPAC instruments are accepted and comprehensible to COPD patients. The difficulty score of C-PPAC is sensitive to duration of daylight and rainfall. Such weather factors must be taken into consideration when evaluating the physical activity behavior using these tools in COPD.Keywords: COPD, physical activity, questionnaire, reliability

Trija Vaidya,1,2 Marc Beaumont,3,4 Claire de Bisschop,1 Lucie Bazerque,5 Camille Le Blanc,6 Anne Vincent,7 Hakima Ouksel,8 Arnaud Chambellan2,9 1Laboratory MOVE (EA6314), Faculty of Sport Sciences, University of Poitiers, Poitiers, France; 2Laboratory “Movement, Interactions, Performance” (EA4334), Faculty of Sport Sciences, University of Nantes, Nantes, France; 3Pulmonary Rehabilitation unit, Morlaix Hospital Centre, Morlaix, France; 4EA3878 (G.E.T.B.O), CHU Brest, Brest, France; 5Institute of Physical Education and Sports Sciences (IFEPSA), Université Catholique de l’Ouest (UCO), Angers, France; 6Physical Medicine and Rehabilitation Department, University Hospital of Nantes, Nantes, France; 7Respiratory Rehabilitation Service, la Tourmaline, UGECAM, Nantes, France; 8Dept of Pulmonary Medicine, Angers University Hospital, Angers, France; 9l’institut du Thorax, University Hospital of Nantes, Nantes, France Background: Measurement of quadriceps muscular force is recommended in individuals with COPD, notably during a pulmonary rehabilitation program (PRP). However, the tools used to measure quadriceps maximal voluntary contraction (QMVC) and the clinical relevance of the results, as well as their interpretation for a given patient, remain a matter of debate. The objective of this study was to estimate the minimally important difference (MID) of QMVC using a fixed dynamometer in individuals with COPD undergoing a PRP. Methods: Individuals with COPD undergoing a PRP were included in this study. QMVC was measured using a dynamometer (MicroFET2) fixed on a rigid support according to a standardized methodology. Exercise capacity was measured by 6-minute walk distance (6MWD) and evaluation of quality of life with St George’s respiratory questionnaire (SGRQ) and Hospital Anxiety and Depression Scale (HADS) total scores. All measures were obtained at baseline and the end of the PRP. The MID was calculated using distribution-based methods. Results: A total of 157 individuals with COPD (age 62.9±9.0 years, forced expiratory volume in 1 second 47.3%±18.6% predicted) were included in this study. At the end of the PRP, the patients had improved their quadriceps force significantly by 8.9±15.6 Nm (P

Trija Vaidya,1,2 Claire de Bisschop,2 Marc Beaumont,3,4 Hakima Ouksel,5 Véronique Jean,6 François Dessables,7 Arnaud Chambellan,1,8 On behalf of IRSR RéhaEffort cohort group 1Explorations Fonctionnelles Respiratoires, l’institut du thorax, CHU de Nantes, 2Université de Poitiers, Laboratoire MOVE EA 6314, F-86000 Poitiers, 3Pulmonary Rehabilitation Unit, Morlaix Hospital Centre, 4European University of Occidental Brittany, EA3878, Brest, 5Service de Pneumologie, CHU d’Angers, Angers, 6Service de Réhabilitation Respiratoire, Soins de Suite et Rééducation, CHU de Nantes, 7Service de Réhabilitation Respiratoire, la Tourmaline, UGECAM, 8Université de Nantes, Laboratory EA 4334 “Mouvement, Interactions, Performance,” Nantes, France Background: The 1-minute sit-to-stand (STS) test could be valuable to assess the level of exercise tolerance in chronic obstructive pulmonary disease (COPD). There is a need to provide the minimal important difference (MID) of this test in pulmonary rehabilitation (PR).Methods: COPD patients undergoing the 1-minute STS test before PR were included. The test was performed at baseline and the end of PR, as well as the 6-minute walk test, and the quadriceps maximum voluntary contraction (QMVC). Home and community-based programs were conducted as recommended. Responsiveness to PR was determined by the difference in the 1-minute STS test between baseline and the end of PR. The MID was evaluated using distribution and anchor-based methods.Results: Forty-eight COPD patients were included. At baseline, the significant predictors of the number of 1-minute STS repetitions were the 6-minute walk distance (6MWD) (r=0.574; P

Yesenia L Franco,* Tanaya R Vaidya,* Sihem Ait-Oudhia Center for Pharmacometrics and Systems Pharmacology, Department of Pharmaceutics, College of Pharmacy, University of Florida, Orlando, FL, USA *These authors contributed equally to this work Abstract: Breast cancer (BC) is a highly prevalent disease, accounting for the second highest number of cancer-related mortalities worldwide. The anthracycline doxorubicin (DOX), isolated from Streptomyces peucetius var. caesius, is a potent chemotherapeutic drug that is successfully used to treat various forms of liquid and solid tumors and is currently approved to treat BC. DOX exerts its effects by intercalation into DNA and inhibition of topoisomerases I and II, causing damage to DNA and the formation of reactive oxygen species (ROS), resulting in the activation of caspases, which ultimately leads to apoptosis. Unfortunately, DOX also can cause cardiotoxicity, with patients only allowed a cumulative lifetime dose of 550 mg/m2. Efforts to decrease cardiotoxicity and to increase the blood circulation time of DOX led to the US Food and Drug Administration (FDA) approval of a PEGylated liposomal formulation (L-DOX), Doxil® (known internationally as Caelyx®). Both exhibit better cardiovascular safety profiles; however, they are not currently FDA approved for the treatment of metastatic BC. Here, we provide detailed insights into the mechanism of action of L-DOX and its most common side effects and highlight results of its use in clinical trials for the treatment of BC as single agent and in combination with other commonly used chemotherapeutics. Keywords: doxil, caelyx, breast cancer, anti-tumor activity, cardiotoxicity

Abstract Background Leishmania META1 has for long been a candidate molecule for involvement in virulence: META1 transcript and protein are up-regulated in metacyclic Leishmania. Yet, how META1 contributes to virulence remains unclear. We sought insights into the possible functions of META1 by studying its evolutionary origins. Results Using multiple criteria including sequence similarity, nucleotide composition, phylogenetic analysis and selection pressure on gene sequence, we present evidence that META1 originated in trypanosomatids as a result of a lateral gene transfer of a bacterial heat-inducible protein, HslJ. Furthermore, within the Leishmania genome, META1 sequence is under negative selection pressure against change/substitution. Using homology modeling of Leishmania META1 based on solved NMR structure of HslJ, we show that META1 and HslJ share a similar structural fold. The best hit for other proteins with similar fold is MxiM, a protein involved in the type III secretion system in Shigella. The striking structural similarity shared by META1, HslJ and MxiM suggests a possibility of shared functions. Upon structural superposition with MxiM, we have observed a putative hydrophobic cavity in META1. Mutagenesis of select hydrophobic residues in this cavity affects the secretion of the secreted acid phosphatase (SAP), indicating META1's involvement in secretory processes in Leishmania. Conclusions Overall, this work uses an evolutionary biology approach, 3D-modeling and site-directed mutagenesis to arrive at new insights into functions of Leishmania META1.

Abstract Background Simple ligation of the vas with suture material and excision of a small vas segment is believed to be the most common vasectomy occlusion technique performed in low-resource settings. Ligation and excision (LE) is associated with a risk of occlusion and contraceptive failure which can be reduced by performing fascial interposition (FI) along with LE. Combining FI with intra luminal thermal cautery could be even more effective. The objective of this study was to determine the surgical vasectomy techniques currently used in five Asian countries and to evaluate the facilitating and limiting factors to introduction and assessment of FI and thermal cautery in these countries. Methods Between December 2003 and February 2004, 3 to 6 major vasectomy centers from Cambodia, Thailand, India, Nepal, and Bangladesh were visited and interviews with 5 to 11 key informants in each country were conducted. Vasectomy techniques performed in each center were observed. Vasectomy techniques using hand-held, battery-driven cautery devices and FI were demonstrated and performed under supervision by local providers. Information about interest and open-mindedness regarding the use of thermal cautery and/or FI was gathered. Results The use of vasectomy was marginal in Thailand and Cambodia. In India, Nepal, and Bangladesh, vasectomy was supported by national reproductive health programs. Most vasectomies were performed using the No-Scalpel Vasectomy (NSV) technique and simple LE. The addition of FI to LE, although largely known, was seldom performed. The main reasons reported were: 1) insufficient surgical skills, 2) time needed to perform the technique, and 3) technique not being mandatory according to country standards. Thermal cautery devices for vasectomy were not available in any selected countries. Pilot hands-on assessment showed that the technique could be safely and effectively performed by Asian providers. However, in addition to provision of supplies, introducing cautery with FI could be associated with the same barriers encountered when introducing FI in combination with LE. Conclusion Further studies assessing the effectiveness, safety, and feasibility of implementation are needed before thermal cautery combined with FI is introduced in Asia on a large scale. Until thermal cautery is introduced in a country, vasectomy providers should practice LE with FI to maximize effectiveness of vasectomy procedure.