Insight into potential mechanisms of hypobaric hypoxia–induced learning and memory deficit – Lessons from rat studies

Impairment of memory is one of the most frequently reported symptoms during sudden hypoxia exposure in human. Cortical atrophy has been linked to the impaired memory function and is suggested to occur with chronic high-altitude exposure. However, the precise molecular mechanism(s) of hypoxia-induced memory impairment remains an enigma. In this work, we review hypoxia-induced learning and memory deficit in human and rat studies. Based on data from rat studies using different protocols of continuous hypoxia, we try to elicit potential mechanisms of hypobaric hypoxia–induced memory deficit

MRE11A isoform expression associated with outcome following radiotherapy in muscle-invasive bladder cancer does not alter cell survival and DNA double-strand break repair following ionising radiation

Background: DNA double strand breaks are the cytotoxic lesions produced by ionising radiation. Critical for the repair of these lesions is the DNA damage response protein MRE11 which, in a complex with RAD50 and NBS1, mediates DNA damage signalling and double-strand break repair. We previously found the presence of an MRE11 germline single nucleotide polymorphism (SNP), rs1805363 (G > A), to be associated with poor outcome following radiotherapy (RT) and increased expression of MRE11 isoform 2 in a limited panel of bladder cancer cell lines and tumours. Objectives: To look for further evidence in support of the SNP/isoform association in a larger panel of germline and tumour samples donated by patients diagnosed with invasive bladder cancer, and to test the hypothesis that bladder cancer cells expressing MRE11 isoform 2 would be more radio resistant than cells expressing MRE11 isoform 1. Methods: Germline DNA from 189 patients with invasive bladder cancer (141 T2, 48 T1) was genotyped for the rs1805363 G > A SNP. Loss of heterozygosity was determined by genotyping tumour DNA in 17GA germline patients. The Cancer Genome Atlas was mined to correlate presence of the GA germline genotype with MRE11 isoform expression. We used colony formation assays and γH2AX foci kinetics after ionising radiation in RT112 MRE11 knockdown cells expressing ectopic MRE11 isoform 1 or 2. Results: Of the 189 germline DNA samples, 22 contained both the A minor allele and G major allele with the remaining wild type containing only the G major allele. LOH was identified in seven of 17 available tumour samples. Tumour MRE11 isoform 2 expression was found to be significantly higher (p = 0.007) in patients’s samples containing the A minor allele compared to those with only the G major allele (n = 23). In the TCGA database we found 16% (66 out of 406) of bladder tumours heterozygous for the SNP and only two homozygous, and a significant relative increase of isoform 2 usage (p = 0.017). We identified no significant difference in radio sensitivity between bladder cancer cells expressing either MRE11 isoform. Conclusions: In this study the MRE11 isoform 2 was not found to be associated with increased cellular sensitivity to radiation. We conclude that the previously reported association between the germline rs1805363 SNP and poor survival in MIBC patients following RT is unlikely to be related to the DNA damage response function of MRE11 isoform 2.</p

Engineered Contrast Agents in a Single Structure for T1-T2 Dual Magnetic Resonance Imaging

[EN] The development of contrast agents (CAs) for Magnetic Resonance Imaging (MRI) with T-1-T-2 dual-mode relaxivity requires the accurate assembly of T-1 and T-2 magnetic centers in a single structure. In this context, we have synthesized a novel hybrid material by monitoring the formation of Prussian Blue analogue Gd(H2O)(4)[Fe(CN)(6)] nanoparticles with tailored shape (from nanocrosses to nanorods) and size, and further protection with a thin and homogeneous silica coating through hydrolysis and polymerization of silicate at neutral pH. The resulting Gd(H2O)(4)[Fe(CN)(6)]@SiO2 magnetic nanoparticles are very stable in biological fluids. Interestingly, this combination of Gd and Fe magnetic centers closely packed in the crystalline network promotes a magnetic synergistic effect, which results in significant improvement of longitudinal relaxivity with regards to soluble Gd3+ chelates, whilst keeping the high transversal relaxivity inherent to the iron component. As a consequence, this material shows excellent activity as MRI CA, improving positive and negative contrasts in T-1- and T-2-weighted MR images, both in in vitro (e.g., phantom) and in vivo (e.g., Sprague-Dawley rats) models. In addition, this hybrid shows a high biosafety profile and has strong ability to incorporate organic molecules on the surface with variable functionality, displaying great potential for further clinical application.Financial support of the Spanish Ministry of Economy and Competitiveness (projects TEC2016-80976-R and SEV-2016-0683) is gratefully acknowledged. Dr E. M. Rivero thanks the Cursol Foundation for a post-doctoral scholarship. A. C. G. also thanks the La Caixa Foundation for a Ph.D. scholarship. We fully appreciate the assistance of the Electron Microscopy Service of the UPV and INSCANNER S.L.Cabrera-García, A.; Checa-Chavarria, E.; Pacheco-Torres, J.; Bernabeu-Sanz, A.; Vidal Moya, JA.; Rivero-Buceta, EM.; Sastre Navarro, GI.... (2018). Engineered Contrast Agents in a Single Structure for T1-T2 Dual Magnetic Resonance Imaging. Nanoscale. 10(14):6349-6360. https://doi.org/10.1039/c7nr07948fS634963601014Bolan, P. J., Nelson, M. T., Yee, D., & Garwood, M. (2005). Imaging in breast cancer: Magnetic resonance spectroscopy. Breast Cancer Research, 7(4). doi:10.1186/bcr1202Mitchell, R. E., Katz, M. H., McKiernan, J. M., & Benson, M. C. (2005). The evaluation and staging of clinically localized prostate cancer. Nature Clinical Practice Urology, 2(8), 356-357. doi:10.1038/ncpuro0260Colombo, M., Carregal-Romero, S., Casula, M. F., Gutiérrez, L., Morales, M. P., Böhm, I. B., … Parak, W. J. (2012). Biological applications of magnetic nanoparticles. Chemical Society Reviews, 41(11), 4306. doi:10.1039/c2cs15337hMi, P., Kokuryo, D., Cabral, H., Wu, H., Terada, Y., Saga, T., … Kataoka, K. (2016). A pH-activatable nanoparticle with signal-amplification capabilities for non-invasive imaging of tumour malignancy. Nature Nanotechnology, 11(8), 724-730. doi:10.1038/nnano.2016.72Cheng, W., Ping, Y., Zhang, Y., Chuang, K.-H., & Liu, Y. (2013). Magnetic Resonance Imaging (MRI) Contrast Agents for Tumor Diagnosis. Journal of Healthcare Engineering, 4(1), 23-46. doi:10.1260/2040-2295.4.1.23Lauffer, R. B. (1987). Paramagnetic metal complexes as water proton relaxation agents for NMR imaging: theory and design. Chemical Reviews, 87(5), 901-927. doi:10.1021/cr00081a003Caravan, P., Ellison, J. J., McMurry, T. J., & Lauffer, R. B. (1999). Gadolinium(III) Chelates as MRI Contrast Agents:  Structure, Dynamics, and Applications. Chemical Reviews, 99(9), 2293-2352. doi:10.1021/cr980440xDavis, M. E., Chen, Z., & Shin, D. M. (2008). Nanoparticle therapeutics: an emerging treatment modality for cancer. Nature Reviews Drug Discovery, 7(9), 771-782. doi:10.1038/nrd2614Lee, N., & Hyeon, T. (2012). Designed synthesis of uniformly sized iron oxide nanoparticles for efficient magnetic resonance imaging contrast agents. Chem. Soc. Rev., 41(7), 2575-2589. doi:10.1039/c1cs15248cHasebroock, K. M., & Serkova, N. J. (2009). Toxicity of MRI and CT contrast agents. Expert Opinion on Drug Metabolism & Toxicology, 5(4), 403-416. doi:10.1517/17425250902873796Khawaja, A. Z., Cassidy, D. B., Al Shakarchi, J., McGrogan, D. G., Inston, N. G., & Jones, R. G. (2015). Revisiting the risks of MRI with Gadolinium based contrast agents—review of literature and guidelines. Insights into Imaging, 6(5), 553-558. doi:10.1007/s13244-015-0420-2Lee, N., Yoo, D., Ling, D., Cho, M. H., Hyeon, T., & Cheon, J. (2015). Iron Oxide Based Nanoparticles for Multimodal Imaging and Magnetoresponsive Therapy. Chemical Reviews, 115(19), 10637-10689. doi:10.1021/acs.chemrev.5b00112Zhou, Z., Bai, R., Munasinghe, J., Shen, Z., Nie, L., & Chen, X. (2017). T1–T2 Dual-Modal Magnetic Resonance Imaging: From Molecular Basis to Contrast Agents. ACS Nano, 11(6), 5227-5232. doi:10.1021/acsnano.7b03075Shin, T.-H., Choi, Y., Kim, S., & Cheon, J. (2015). Recent advances in magnetic nanoparticle-based multi-modal imaging. Chemical Society Reviews, 44(14), 4501-4516. doi:10.1039/c4cs00345dBae, K. H., Kim, Y. B., Lee, Y., Hwang, J., Park, H., & Park, T. G. (2010). Bioinspired Synthesis and Characterization of Gadolinium-Labeled Magnetite Nanoparticles for Dual ContrastT1- andT2-Weighted Magnetic Resonance Imaging. Bioconjugate Chemistry, 21(3), 505-512. doi:10.1021/bc900424uPeng, Y.-K., Lui, C. N. P., Chen, Y.-W., Chou, S.-W., Raine, E., Chou, P.-T., … Tsang, S. C. E. (2017). Engineering of Single Magnetic Particle Carrier for Living Brain Cell Imaging: A Tunable T1-/T2-/Dual-Modal Contrast Agent for Magnetic Resonance Imaging Application. Chemistry of Materials, 29(10), 4411-4417. doi:10.1021/acs.chemmater.7b00884Choi, J., Lee, J.-H., Shin, T.-H., Song, H.-T., Kim, E. Y., & Cheon, J. (2010). Self-Confirming «AND» Logic Nanoparticles for Fault-Free MRI. Journal of the American Chemical Society, 132(32), 11015-11017. doi:10.1021/ja104503gShin, T.-H., Choi, J., Yun, S., Kim, I.-S., Song, H.-T., Kim, Y., … Cheon, J. (2014). T1andT2Dual-Mode MRI Contrast Agent for Enhancing Accuracy by Engineered Nanomaterials. ACS Nano, 8(4), 3393-3401. doi:10.1021/nn405977tCheng, K., Yang, M., Zhang, R., Qin, C., Su, X., & Cheng, Z. (2014). Hybrid Nanotrimers for Dual T1 and T2-Weighted Magnetic Resonance Imaging. ACS Nano, 8(10), 9884-9896. doi:10.1021/nn500188yZhou, Z., Huang, D., Bao, J., Chen, Q., Liu, G., Chen, Z., … Gao, J. (2012). A Synergistically EnhancedT1-T2Dual-Modal Contrast Agent. Advanced Materials, 24(46), 6223-6228. doi:10.1002/adma.201203169Huang, G., Li, H., Chen, J., Zhao, Z., Yang, L., Chi, X., … Gao, J. (2014). Tunable T1and T2contrast abilities of manganese-engineered iron oxide nanoparticles through size control. Nanoscale, 6(17), 10404. doi:10.1039/c4nr02680bPerrier, M., Kenouche, S., Long, J., Thangavel, K., Larionova, J., Goze-Bac, C., … Guari, Y. (2013). Investigation on NMR Relaxivity of Nano-Sized Cyano-Bridged Coordination Polymers. Inorganic Chemistry, 52(23), 13402-13414. doi:10.1021/ic401710jPerera, V. S., Yang, L. D., Hao, J., Chen, G., Erokwu, B. O., Flask, C. A., … Huang, S. D. (2014). Biocompatible Nanoparticles of KGd(H2O)2[Fe(CN)6]·H2O with Extremely HighT1-Weighted Relaxivity Owing to Two Water Molecules Directly Bound to the Gd(III) Center. Langmuir, 30(40), 12018-12026. doi:10.1021/la501985pCai, X., Gao, W., Ma, M., Wu, M., Zhang, L., Zheng, Y., … Shi, J. (2015). A Prussian Blue-Based Core-Shell Hollow-Structured Mesoporous Nanoparticle as a Smart Theranostic Agent with Ultrahigh pH-Responsive Longitudinal Relaxivity. Advanced Materials, 27(41), 6382-6389. doi:10.1002/adma.201503381Yang, L., Zhou, Z., Liu, H., Wu, C., Zhang, H., Huang, G., … Gao, J. (2015). Europium-engineered iron oxide nanocubes with high T1and T2contrast abilities for MRI in living subjects. Nanoscale, 7(15), 6843-6850. doi:10.1039/c5nr00774gCabrera-García, A., Vidal-Moya, A., Bernabeu, Á., Sánchez-González, J., Fernández, E., & Botella, P. (2015). Gd–Si oxide mesoporous nanoparticles with pre-formed morphology prepared from a Prussian blue analogue template. Dalton Transactions, 44(31), 14034-14041. doi:10.1039/c5dt01928aCabrera-García, A., Vidal-Moya, A., Bernabeu, Á., Pacheco-Torres, J., Checa-Chavarria, E., Fernández, E., & Botella, P. (2016). Gd-Si Oxide Nanoparticles as Contrast Agents in Magnetic Resonance Imaging. Nanomaterials, 6(6), 109. doi:10.3390/nano6060109Botella, P., Corma, A., & Quesada, M. (2012). Synthesis of ordered mesoporous silica templated with biocompatible surfactants and applications in controlled release of drugs. Journal of Materials Chemistry, 22(13), 6394. doi:10.1039/c2jm16291aMascharak, P. K. (1986). Convenient synthesis of tris(tetraethylammonium) hexacyanoferrate(III) and its use as an oxidant with tunable redox potential. Inorganic Chemistry, 25(3), 245-247. doi:10.1021/ic00223a001Clemments, A. M., Muniesa, C., Landry, C. C., & Botella, P. (2014). Effect of surface properties in protein corona development on mesoporous silica nanoparticles. RSC Adv., 4(55), 29134-29138. doi:10.1039/c4ra03277bOyane, A., Kim, H.-M., Furuya, T., Kokubo, T., Miyazaki, T., & Nakamura, T. (2003). Preparation and assessment of revised simulated body fluids. Journal of Biomedical Materials Research, 65A(2), 188-195. doi:10.1002/jbm.a.10482Blüml, S., Schad, L. R., Stepanow, B., & Lorenz, W. J. (1993). Spin-lattice relaxation time measurement by means of a TurboFLASH technique. Magnetic Resonance in Medicine, 30(3), 289-295. doi:10.1002/mrm.1910300304Hennig, J., & Friedburg, H. (1988). Clinical applications and methodological developments of the RARE technique. Magnetic Resonance Imaging, 6(4), 391-395. doi:10.1016/0730-725x(88)90475-4Hennig, J., Nauerth, A., & Friedburg, H. (1986). RARE imaging: A fast imaging method for clinical MR. Magnetic Resonance in Medicine, 3(6), 823-833. doi:10.1002/mrm.1910030602Yamada, M., & Yonekura, S. (2009). Nanometric Metal−Organic Framework of Ln[Fe(CN)6]: Morphological Analysis and Thermal Conversion Dynamics by Direct TEM Observation. The Journal of Physical Chemistry C, 113(52), 21531-21537. doi:10.1021/jp907180eNavarro, M. C., Pannunzio-Miner, E. V., Pagola, S., Gómez, M. I., & Carbonio, R. E. (2005). Structural refinement of Nd[Fe(CN)6]·4H2O and study of NdFeO3 obtained by its oxidative thermal decomposition at very low temperatures. Journal of Solid State Chemistry, 178(3), 847-854. doi:10.1016/j.jssc.2004.11.026Ding, Y., Chu, X., Hong, X., Zou, P., & Liu, Y. (2012). The infrared fingerprint signals of silica nanoparticles and its application in immunoassay. Applied Physics Letters, 100(1), 013701. doi:10.1063/1.3673549Botella, P., Abasolo, I., Fernández, Y., Muniesa, C., Miranda, S., Quesada, M., … Corma, A. (2011). Surface-modified silica nanoparticles for tumor-targeted delivery of camptothecin and its biological evaluation. Journal of Controlled Release, 156(2), 246-257. doi:10.1016/j.jconrel.2011.06.039Na, H. B., Lee, J. H., An, K., Park, Y. I., Park, M., Lee, I. S., … Hyeon, T. (2007). Development of aT1 Contrast Agent for Magnetic Resonance Imaging Using MnO Nanoparticles. Angewandte Chemie International Edition, 46(28), 5397-5401. doi:10.1002/anie.200604775Deng, Y., Li, E., Cheng, X., Zhu, J., Lu, S., Ge, C., … Pan, Y. (2016). Facile preparation of hybrid core–shell nanorods for photothermal and radiation combined therapy. Nanoscale, 8(7), 3895-3899. doi:10.1039/c5nr09102kBottrill, M., Kwok, L., & Long, N. J. (2006). Lanthanides in magnetic resonance imaging. Chemical Society Reviews, 35(6), 557. doi:10.1039/b516376pZhang, W., Martinelli, J., Peters, J. A., van Hengst, J. M. A., Bouwmeester, H., Kramer, E., … Djanashvili, K. (2017). Surface PEG Grafting Density Determines Magnetic Relaxation Properties of Gd-Loaded Porous Nanoparticles for MR Imaging Applications. ACS Applied Materials & Interfaces, 9(28), 23458-23465. doi:10.1021/acsami.7b05912Li, Y., Chen, T., Tan, W., & Talham, D. R. (2014). Size-Dependent MRI Relaxivity and Dual Imaging with Eu0.2Gd0.8PO4·H2O Nanoparticles. Langmuir, 30(20), 5873-5879. doi:10.1021/la500602xT. L. Riss , R. A.Moravec , A. L.Niles , S.Duellman , H. A.Benink , T. J.Worzella and L.Minor , Cell Viability Assays , in Assay Guidance Manual , Eli Lilly & Company and the National Center for Advancing Translational Sciences , Bethesda, MD , 2012Mahmoudi, M., Lynch, I., Ejtehadi, M. R., Monopoli, M. P., Bombelli, F. B., & Laurent, S. (2011). Protein−Nanoparticle Interactions: Opportunities and Challenges. Chemical Reviews, 111(9), 5610-5637. doi:10.1021/cr100440gLu, J., Liong, M., Li, Z., Zink, J. I., & Tamanoi, F. (2010). Biocompatibility, Biodistribution, and Drug-Delivery Efficiency of Mesoporous Silica Nanoparticles for Cancer Therapy in Animals. Small, 6(16), 1794-1805. doi:10.1002/smll.20100053

Elemental hydrochemistry assessment on its variation and quality status in Langat River, Western Peninsular Malaysia.

This paper discusses the hydrochemistry variation and its quality status in Langat River, based on the chemistry of major ions, metal concentrations and suitability for drinking purposes. Water samples were collected from 30 different stations to assess their hydrochemical characteristics. The physico-chemical parameters selected were temperature, electrical conductivity, total dissolved solids (TDS), salinity, dissolved oxygen , pH, redox potential, HCO3, Cl, SO4, NO3, Ca, Na, K, Mg, 27Al, 138Ba, 9Be, 111Cd, 59Co, 63Cu, 52Cr, 57Fe, 55Mn, 60Ni, 208Pb, 80Se and 66Zn to investigate the variation of the constituents in the river water. Most of the parameters comply with the Drinking Water Quality Standard of the World Health Organization and the Malaysian National Standard for Drinking Water Quality by the Malaysia Ministry of Health except for EC, TDS, Cl, HCO3, SO4, Na, Mg, Al, Fe and Se. The results show that the Langat River is unsuitable for drinking purposes directly without treatment

How do religious norms diffuse? Institutional translation and international change in a post-secular world society

This article draws from Habermasian post-secular theory to broaden the scope of Constructivist research on norm dynamics beyond its current Western-centric focus. In an increasingly post-secular world society, we conceptualize the mechanism of institutional translation to explain processes of norm diffusion whereby culturally situated ‘thick’ norms acquire a ‘thinner’ ethical status via a dialogical process of normative contestation across diverse ethical perspectives. Institutional translation differs from, but also complements, mechanisms of norm diffusion, such as persuasion and localization, by illustrating how norms conceived and promoted by non-Western religious-based actors can acquire global legitimacy within the institutions of the international liberal order. The article investigates the explanatory value of this framework through an empirical analysis of two contrasting cases of norm promotion by the Organization of Islamic Conference at the United Nations. The first case considers the global diffusion of the norm of dialogue of civilizations as an example of successful institutional translation. The second case illustrates the failed diffusion of the norm against th

Measurement of the Z/gamma* + b-jet cross section in pp collisions at 7 TeV

The production of b jets in association with a Z/gamma* boson is studied using proton-proton collisions delivered by the LHC at a centre-of-mass energy of 7 TeV and recorded by the CMS detector. The inclusive cross section for Z/gamma* + b-jet production is measured in a sample corresponding to an integrated luminosity of 2.2 inverse femtobarns. The Z/gamma* + b-jet cross section with Z/gamma* to ll (where ll = ee or mu mu) for events with the invariant mass 60 < M(ll) < 120 GeV, at least one b jet at the hadron level with pT > 25 GeV and abs(eta) < 2.1, and a separation between the leptons and the jets of Delta R > 0.5 is found to be 5.84 +/- 0.08 (stat.) +/- 0.72 (syst.) +(0.25)/-(0.55) (theory) pb. The kinematic properties of the events are also studied and found to be in agreement with the predictions made by the MadGraph event generator with the parton shower and the hadronisation performed by PYTHIA.Comment: Submitted to the Journal of High Energy Physic

All-arthroscopic versus mini-open repair of small or moderate-sized rotator cuff tears: A protocol for a randomized trial [NCT00128076]

BACKGROUND: Rotator cuff tears are the most common source of shoulder pain and disability. Only poor quality studies have compared mini-open to arthroscopic repair, leaving surgeons with inadequate evidence to support optimal, minimally-invasive repair. METHODS/DESIGN: This randomized, multi-centre, national trial will determine whether an arthroscopic or mini-open repair provides better quality of life for patients with small or moderate-sized rotator cuff tears. A national consensus meeting of investigators in the Joint Orthopaedic Initiative for National Trials of the Shoulder (JOINTS Canada) identified this question as the top priority for shoulder surgeons across Canada. The primary outcome measure is a valid quality-of-life scale (Western Ontario Rotator Cuff (WORC)) that addresses 5 domains of health affected by rotator cuff disease. Secondary outcomes will assess rotator cuff functionality (ROM, strength, Constant score), secondary dimensions of health (general health status (SF-12) and work limitations), and repair integrity (MRI). Outcomes are measured at baseline, at 6 weeks, 3, 6, 12, and 24 months post-operatively by blinded research assistants and musculoskeletal radiologists. Patients (n = 250) with small or medium-sized cuff tears identified by clinical examination and MRI who meet eligibility criteria will be recruited. This sample size will provide 80% power to statistically detect a clinically important difference of 20% in WORC scores between procedures after controlling for baseline WORC score (α = 0.05). A central methods centre will manage randomization, data management, and monitoring under supervision of experienced epidemiologists. Surgeons will participate in either conventional or expertise-based designs according to defined criteria to avoid biases from differential surgeon expertise. Mini-open or all-arthroscopic repair procedures will be performed according to a standardized protocol. Central Adjudication (of cases), Trial Oversight and Safety Committees will monitor trial conduct. We will use an analysis of covariance (ANCOVA), where the baseline WORC score is used as a covariate, to compare the quality of life (WORC score) at 2 years post-operatively. As a secondary analysis, we will conduct the same statistical test but will include age and tear size as covariates with the baseline score. Enrollment will require 2 years and follow-up an additional 2 years. The trial will commence when funding is in place. DISCUSSION: These results will have immediate impact on the practice behaviors of practicing surgeons and surgical trainees at JOINTS centres across Canada. JOINTS Canada is actively engaged in knowledge exchange and will publish and present findings internationally to facilitate wider application. This trial will establish definitive evidence on this question at an international level

Growth Inhibition of Human Gynecologic and Colon Cancer Cells by Phyllanthus watsonii through Apoptosis Induction

Phyllanthus watsonii Airy Shaw is an endemic plant found in Peninsular Malaysia. Although there are numerous reports on the anti cancer properties of other Phyllanthus species, published information on the cytotoxicity of P. watsonii are very limited. The present study was carried out with bioassay-guided fractionation approach to evaluate the cytotoxicity and apoptosis induction capability of the P. watsonii extracts and fractions on human gynecologic (SKOV-3 and Ca Ski) and colon (HT-29) cancer cells. P. watsonii extracts exhibited strong cytotoxicity on all the cancer cells studied with IC50 values of ≤ 20.0 µg/mL. Hexane extract of P. watsonii was further subjected to bioassay-guided fractionation and yielded 10 fractions (PW-1→PW-10). PW-4→PW-8 portrayed stronger cytotoxic activity and was further subjected to bioassay-guided fractionation and resulted with 8 sub-fractions (PPWH-1→PPWH-8). PPWH-7 possessed greatest cytotoxicity (IC50 values ranged from 0.66 – 0.83 µg/mL) and was selective on the cancer cells studied. LC-MS/MS analysis of PPWH-7 revealed the presence of ellagic acid, geranic acid, glochidone, betulin, phyllanthin and sterol glucoside. Marked morphological changes, ladder-like appearance of DNA and increment in caspase-3 activity indicating apoptosis were clearly observed in both human gynecologic and colon cancer cells treated with P. watsonii especially with PPWH-7. The study also indicated that P. watsonii extracts arrested cell cycle at different growth phases in SKOV-3, Ca Ski and HT-29 cells. Cytotoxic and apoptotic potential of the endemic P. watsonii was investigated for the first time by bioassay-guided approach. These results demonstrated that P. watsonii selectively inhibits the growth of SKOV-3, Ca Ski and HT-29 cells through apoptosis induction and cell cycle modulation. Hence, P. watsonii has the potential to be further exploited for the discovery and development of new anti cancer drugs

Pooled analysis of WHO Surgical Safety Checklist use and mortality after emergency laparotomy

Background The World Health Organization (WHO) Surgical Safety Checklist has fostered safe practice for 10 years, yet its place in emergency surgery has not been assessed on a global scale. The aim of this study was to evaluate reported checklist use in emergency settings and examine the relationship with perioperative mortality in patients who had emergency laparotomy. Methods In two multinational cohort studies, adults undergoing emergency laparotomy were compared with those having elective gastrointestinal surgery. Relationships between reported checklist use and mortality were determined using multivariable logistic regression and bootstrapped simulation. Results Of 12 296 patients included from 76 countries, 4843 underwent emergency laparotomy. After adjusting for patient and disease factors, checklist use before emergency laparotomy was more common in countries with a high Human Development Index (HDI) (2455 of 2741, 89.6 per cent) compared with that in countries with a middle (753 of 1242, 60.6 per cent; odds ratio (OR) 0.17, 95 per cent c.i. 0.14 to 0.21, P <0001) or low (363 of 860, 422 per cent; OR 008, 007 to 010, P <0.001) HDI. Checklist use was less common in elective surgery than for emergency laparotomy in high-HDI countries (risk difference -94 (95 per cent c.i. -11.9 to -6.9) per cent; P <0001), but the relationship was reversed in low-HDI countries (+121 (+7.0 to +173) per cent; P <0001). In multivariable models, checklist use was associated with a lower 30-day perioperative mortality (OR 0.60, 0.50 to 073; P <0.001). The greatest absolute benefit was seen for emergency surgery in low- and middle-HDI countries. Conclusion Checklist use in emergency laparotomy was associated with a significantly lower perioperative mortality rate. Checklist use in low-HDI countries was half that in high-HDI countries.Peer reviewe