ACL injuries identifiable for pre-participation imagiological analysis: Risk factors

Identification of pre-participation risk factors for noncontact anterior cruciate ligament (ACL) injuries has been attracting a great deal of interest in the sports medicine and traumatology communities. Appropriate methods that enable predicting which patients could benefit from pre- ventive strategies are most welcome. This would enable athlete-specific training and conditioning or tailored equipment in order to develop appropriate strategies to reduce incidence of injury. In order to accomplish these goals, the ideal system should be able to assess both anatomic and functional features. Complementarily, the screening method must be cost-effective and suited for widespread application. Anatomic study protocol requiring only standard X rays could answer some of such demands. Dynamic MRI/CT evaluation and electronically assisted pivot-shift evaluation can be powerful tools providing complementary information. These upcoming insights, when validated and properly combined, envision changing pre-participation knee examination in the near future. Herein different methods (validated or under research) aiming to improve the capacity to identify persons/athletes with higher risk for ACL injury are overviewed.

Opioid but not nonopioid stress-induced analgesia is enhanced following prenatal exposure to ethanol

Two neurochemically distinct forms of stress-induced analgesia were examined in adult rats following prenatal ethanol exposure. Rats were exposed to ethanol during the last 2 weeks of gestation through a liquid diet presented to the dams. Analgesia testing was conducted when the offspring were 150–210 days of age. Two forms of footshock stress were administered; one that resulted in a naloxone-sensitive (opioid-mediated) analgesia and one that resulted in a naloxone-insensitive (nonopioid) form of analgesia. Rats prenatally exposed to ethanol demonstrated significantly enhanced opioid-mediated analgesia, but unaltered nonpoioid analgesia compared to controls. These results confirm previous findings that prenatal exposure to ethanol leads to long-term alterations in responding to some, but not all forms of stress. The possibility that prenatal exposure to ethanol leads to perturbations in the endogenous opioid systems is discussed.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/46435/1/213_2004_Article_BF00427329.pd

Population Structure and Transmission Dynamics of Plasmodium vivax in the Republic of Korea Based on Microsatellite DNA Analysis

Vivax malaria is widely prevalent, mainly in Asia and South America with 390 million reported cases in 2009. Worldwide, in the same year, 2.85 billion people were at risk. Plasmodium vivax is prevalent not only in tropical and subtropical areas but also in temperate areas where there are no mosquitoes in cold seasons. While most malaria researchers are focusing their studies on the parasite in tropical areas, we examined the characteristics of P. vivax in South Korea (temperate area) temporally, using 10 highly polymorphic microsatellite DNA (a short tandem repeat DNA sequence) in the parasite genome, and highlighted the differences between the tropical and temperate populations. We found that the South Korean P. vivax population had low genetic diversity and low recombination rates in comparison to tropical P. vivax populations that had been reported. We also found that some of the parasite clones in the population were changing from 1994 to 2008, evidence suggesting the continual introduction of the parasite from other populations, probably from North Korea. Polymorphic DNA markers of the P. vivax parasite are useful tools for estimating the situation of its transmission in endemic areas

Assessment of rotatory laxity in anterior cruciate ligament-deficient knees using magnetic resonance imaging with Porto-knee testing device

Purpose Objective evaluation of both antero-posterior translation and rotatory laxity of the knee remains a target to be accomplished. This is true for both preoperative planning and postoperative assessment of different ACL reconstruction emerging techniques. The ideal measurement tool should be simple, accurate and reproducible, while enabling to assess both ‘‘anatomy’’ and ‘‘function’’ during the same examination. The purpose of this study is to evaluate the clinical effectiveness of a new in-housedeveloped testing device, the so-called Porto-knee testing device (PKTD). The PKTD is aimed to be used on the evaluation of both antero-posterior and rotatory laxity of the knee during MRI exams. Methods Between 2008 and 2010, 33 patients with ACLdeficient knees were enrolled for the purpose of this study. All patients were evaluated in the office and under anesthesia with Lachman test, lateral pivot-shift test and anterior drawer test. All cases were studied preoperatively with KT-1000 and MRI with PKTD, and examinations performed by independent observers blinded for clinical evaluation. During MRI, we have used a PKTD that applies antero-posterior translation and permits free tibial rotation through a standardized pressure (46.7 kPa) in the proximal posterior region of the leg. Measurements were taken for both knees and comparing side-to-side. Five patients with partial ruptures were excluded from the group of 33. Results For the 28 remaining patients, 3 women and 25 men, with mean age of 33.4 ± 9.4 years, 13 left and 15 right knees were tested. No significant correlation was noticed for Lachman test and PKTD results (n.s.). Pivot-shift had a strong positive correlation with the difference in anterior translation registered in lateral and medial tibia plateaus of injured knees (cor. coefficient = 0.80; p\0.05), and with the difference in this parameter as compared to side-to-side (cor. coefficient = 0.83; p\0.05). Considering the KT-1000 difference between injured and healthy knees, a very strong positive correlation was found for side-to-side difference in medial (cor. coeffi- cient = 0.73; p\0.05) and lateral (cor. coefficient = 0.5; p\0.05) tibial plateau displacement using PKTD. Conclusion The PKTD proved to be a reliable tool in assessment of antero-posterior translation (comparing with KT-1000) and rotatory laxity (compared with lateral pivotshift under anesthesia) of the ACL-deficient knee during MRI examinatio

The Evolution of Compact Binary Star Systems

We review the formation and evolution of compact binary stars consisting of white dwarfs (WDs), neutron stars (NSs), and black holes (BHs). Binary NSs and BHs are thought to be the primary astrophysical sources of gravitational waves (GWs) within the frequency band of ground-based detectors, while compact binaries of WDs are important sources of GWs at lower frequencies to be covered by space interferometers (LISA). Major uncertainties in the current understanding of properties of NSs and BHs most relevant to the GW studies are discussed, including the treatment of the natal kicks which compact stellar remnants acquire during the core collapse of massive stars and the common envelope phase of binary evolution. We discuss the coalescence rates of binary NSs and BHs and prospects for their detections, the formation and evolution of binary WDs and their observational manifestations. Special attention is given to AM CVn-stars -- compact binaries in which the Roche lobe is filled by another WD or a low-mass partially degenerate helium-star, as these stars are thought to be the best LISA verification binary GW sources.Comment: 105 pages, 18 figure

Role of Combination Antiplatelet and Anticoagulation Therapy in Diabetes Mellitus and Cardiovascular Disease: Insights From the COMPASS Trial

BACKGROUND: Patients with established coronary artery disease or peripheral artery disease often have diabetes mellitus. These patients are at high risk of future vascular events.METHODS: In a prespecified analysis of the COMPASS trial (Cardiovascular Outcomes for People Using Anticoagulation Strategies), we compared the effects of rivaroxaban (2.5 mg twice daily) plus aspirin (100 mg daily) versus placebo plus aspirin in patients with diabetes mellitus versus without diabetes mellitus in preventing major vascular events. The primary efficacy end point was the composite of cardiovascular death, myocardial infarction, or stroke. Secondary end points included all-cause mortality and all major vascular events (cardiovascular death, myocardial infarction, stroke, or major adverse limb events, including amputation). The primary safety end point was a modification of the International Society on Thrombosis and Haemostasis criteria for major bleeding.RESULTS: There were 10 341 patients with diabetes mellitus and 17 054 without diabetes mellitus in the overall trial. A consistent and similar relative risk reduction was seen for benefit of rivaroxaban plus aspirin (n=9152) versus placebo plus aspirin (n=9126) in patients both with (n=6922) and without (n=11 356) diabetes mellitus for the primary efficacy end point (hazard ratio, 0.74, P=0.002; and hazard ratio, 0.77,P=0.005, respectively, Pinteraction=0.77) and all-cause mortality (hazard ratio, 0.81, P=0.05; and hazard ratio, 0.84,P=0.09, respectively; Pinteraction=0.82). However, although the absolute risk reductions appeared numerically larger in patients with versus without diabetes mellitus, both subgroups derived similar benefit (2.3% versus 1.4% for the primary efficacy end point at 3 years, Gail-Simon qualitative  PinteractionPinteraction=0.02; 2.7% versus 1.7% for major vascular events, PinteractionPinteraction=0.001).CONCLUSIONS: In stable atherosclerosis, the combination of aspirin plus rivaroxaban 2.5 mg twice daily provided a similar relative degree of benefit on coronary, cerebrovascular, and peripheral end points in patients with and without diabetes mellitus. Given their higher baseline risk, the absolute benefits appeared larger in those with diabetes mellitus, including a 3-fold greater reduction in all-cause mortality. Registration: Unique identifier: NCT01776424.</div

Different rates of spontaneous mutation of chloroplastic and nuclear viroids as determined by high-fidelity ultra-deep sequencing

[EN] Mutation rates vary by orders of magnitude across biological systems, being higher for simpler genomes. The simplest known genomes correspond to viroids, subviral plant replicons constituted by circular non-coding RNAs of few hundred bases. Previous work has revealed an extremely high mutation rate for chrysanthemum chlorotic mottle viroid, a chloroplastreplicating viroid. However, whether this is a general feature of viroids remains unclear. Here, we have used high-fidelity ultra-deep sequencing to determine the mutation rate in a common host (eggplant) of two viroids, each representative of one family: the chloroplastic eggplant latent viroid (ELVd, Avsunviroidae) and the nuclear potato spindle tuber viroid (PSTVd, Pospiviroidae). This revealed higher mutation frequencies in ELVd than in PSTVd, as well as marked differences in the types of mutations produced. Rates of spontaneous mutation, quantified in vivo using the lethal mutation method, ranged from 1/1000 to 1/800 for ELVd and from 1/7000 to 1/3800 for PSTVd depending on sequencing run. These results suggest that extremely high mutability is a common feature of chloroplastic viroids, whereas the mutation rates of PSTVd and potentially other nuclear viroids appear significantly lower and closer to those of some RNA viruses.This work was supported by the European Research Council (erc.europa.eu; ERC-2011-StG-281191-VIRMUT to RS), the Spanish Ministerio de Economia y Competitividad (www.mineco.gob.es; BFU2013-41329 grant to RS, BFU2014-56812-P grant to RF, and a predoctoral fellowship to ALC), and the Spanish Junta de Comunidades de Castilla-La Mancha (www.castillalamancha.es;postdoctoral fellowship to CB). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.López-Carrasco, MA.; Ballesteros Martínez, C.; Sentandreu, V.; Delgado Villar, SG.; Gago Zachert, SP.; Flores Pedauye, R.; Sanjuan Verdeguer, R. (2017). Different rates of spontaneous mutation of chloroplastic and nuclear viroids as determined by high-fidelity ultra-deep sequencing. PLoS Pathogens. 13(9):1-17. https://doi.org/10.1371/journal.ppat.1006547S117139Ganai, R. A., & Johansson, E. (2016). DNA Replication—A Matter of Fidelity. Molecular Cell, 62(5), 745-755. doi:10.1016/j.molcel.2016.05.003Lynch, M. (2010). Evolution of the mutation rate. Trends in Genetics, 26(8), 345-352. doi:10.1016/j.tig.2010.05.003Sanjuán, R., & Domingo-Calap, P. (2016). Mechanisms of viral mutation. Cellular and Molecular Life Sciences, 73(23), 4433-4448. doi:10.1007/s00018-016-2299-6Gago, S., Elena, S. F., Flores, R., & Sanjuan, R. (2009). Extremely High Mutation Rate of a Hammerhead Viroid. Science, 323(5919), 1308-1308. doi:10.1126/science.1169202Flores, R., Gago-Zachert, S., Serra, P., Sanjuán, R., & Elena, S. F. (2014). Viroids: Survivors from the RNA World? Annual Review of Microbiology, 68(1), 395-414. doi:10.1146/annurev-micro-091313-103416Flores, R., Minoia, S., Carbonell, A., Gisel, A., Delgado, S., López-Carrasco, A., … Di Serio, F. (2015). Viroids, the simplest RNA replicons: How they manipulate their hosts for being propagated and how their hosts react for containing the infection. Virus Research, 209, 136-145. doi:10.1016/j.virusres.2015.02.027Steger, G., & Perreault, J.-P. (2016). Structure and Associated Biological Functions of Viroids. Advances in Virus Research, 141-172. doi:10.1016/bs.aivir.2015.11.002Diener, T. O. (1989). Circular RNAs: relics of precellular evolution? Proceedings of the National Academy of Sciences, 86(23), 9370-9374. doi:10.1073/pnas.86.23.9370Ambrós, S., Hernández, C., & Flores, R. (1999). Rapid generation of genetic heterogeneity in progenies from individual cDNA clones of peach latent mosaic viroid in its natural host The data reported in this paper are in the EMBL nucleotide sequence database and assigned the accession nos AJ241818–AJ241850. Journal of General Virology, 80(8), 2239-2252. doi:10.1099/0022-1317-80-8-2239Navarro, J.-A., Vera, A., & Flores, R. (2000). A Chloroplastic RNA Polymerase Resistant to Tagetitoxin Is Involved in Replication of Avocado Sunblotch Viroid. Virology, 268(1), 218-225. doi:10.1006/viro.1999.0161Rodio, M.-E., Delgado, S., De Stradis, A., Gómez, M.-D., Flores, R., & Di Serio, F. (2007). A Viroid RNA with a Specific Structural Motif Inhibits Chloroplast Development. The Plant Cell, 19(11), 3610-3626. doi:10.1105/tpc.106.049775Carbonell, A., De la Peña, M., Flores, R., & Gago, S. (2006). Effects of the trinucleotide preceding the self-cleavage site on eggplant latent viroid hammerheads: differences in co- and post-transcriptional self-cleavage may explain the lack of trinucleotide AUC in most natural hammerheads. Nucleic Acids Research, 34(19), 5613-5622. doi:10.1093/nar/gkl717Hutchins, C. J., Rathjen, P. D., Forster, A. C., & Symons, R. H. (1986). Self-cleavage of plus and minus RNA transcripts of avocado sunblotch viroid. Nucleic Acids Research, 14(9), 3627-3640. doi:10.1093/nar/14.9.3627PRODY, G. A., BAKOS, J. T., BUZAYAN, J. M., SCHNEIDER, I. R., & BRUENING, G. (1986). Autolytic Processing of Dimeric Plant Virus Satellite RNA. Science, 231(4745), 1577-1580. doi:10.1126/science.231.4745.1577Nohales, M.-A., Molina-Serrano, D., Flores, R., & Daros, J.-A. (2012). Involvement of the Chloroplastic Isoform of tRNA Ligase in the Replication of Viroids Belonging to the Family Avsunviroidae. Journal of Virology, 86(15), 8269-8276. doi:10.1128/jvi.00629-12Branch, A. D., Benenfeld, B. J., & Robertson, H. D. (1988). Evidence for a single rolling circle in the replication of potato spindle tuber viroid. Proceedings of the National Academy of Sciences, 85(23), 9128-9132. doi:10.1073/pnas.85.23.9128Daros, J.-A., & Flores, R. (2004). Arabidopsis thaliana has the enzymatic machinery for replicating representative viroid species of the family Pospiviroidae. Proceedings of the National Academy of Sciences, 101(17), 6792-6797. doi:10.1073/pnas.0401090101Feldstein, P. A., Hu, Y., & Owens, R. A. (1998). Precisely full length, circularizable, complementary RNA: An infectious form of potato spindle tuber viroid. Proceedings of the National Academy of Sciences, 95(11), 6560-6565. doi:10.1073/pnas.95.11.6560Gas, M.-E., Hernández, C., Flores, R., & Daròs, J.-A. (2007). Processing of Nuclear Viroids In Vivo: An Interplay between RNA Conformations. PLoS Pathogens, 3(11), e182. doi:10.1371/journal.ppat.0030182Nohales, M.-A., Flores, R., & Daros, J.-A. (2012). Viroid RNA redirects host DNA ligase 1 to act as an RNA ligase. Proceedings of the National Academy of Sciences, 109(34), 13805-13810. doi:10.1073/pnas.1206187109Brass, J. R. J., Owens, R. A., Matoušek, J., & Steger, G. (2017). Viroid quasispecies revealed by deep sequencing. RNA Biology, 14(3), 317-325. doi:10.1080/15476286.2016.1272745Bull, J. J., Sanjuán, R., & Wilke, C. O. (2007). Theory of Lethal Mutagenesis for Viruses. Journal of Virology, 81(6), 2930-2939. doi:10.1128/jvi.01624-06Cuevas, J. M., González-Candelas, F., Moya, A., & Sanjuán, R. (2009). Effect of Ribavirin on the Mutation Rate and Spectrum of Hepatitis C Virus In Vivo. Journal of Virology, 83(11), 5760-5764. doi:10.1128/jvi.00201-09Ribeiro, R. M., Li, H., Wang, S., Stoddard, M. B., Learn, G. H., Korber, B. T., … Perelson, A. S. (2012). Quantifying the Diversification of Hepatitis C Virus (HCV) during Primary Infection: Estimates of the In Vivo Mutation Rate. PLoS Pathogens, 8(8), e1002881. doi:10.1371/journal.ppat.1002881Acevedo, A., Brodsky, L., & Andino, R. (2013). Mutational and fitness landscapes of an RNA virus revealed through population sequencing. Nature, 505(7485), 686-690. doi:10.1038/nature12861Cuevas, J. M., Geller, R., Garijo, R., López-Aldeguer, J., & Sanjuán, R. (2015). Extremely High Mutation Rate of HIV-1 In Vivo. PLOS Biology, 13(9), e1002251. doi:10.1371/journal.pbio.1002251Acevedo, A., & Andino, R. (2014). Library preparation for highly accurate population sequencing of RNA viruses. Nature Protocols, 9(7), 1760-1769. doi:10.1038/nprot.2014.118Kennedy, S. R., Schmitt, M. W., Fox, E. J., Kohrn, B. F., Salk, J. J., Ahn, E. H., … Loeb, L. A. (2014). Detecting ultralow-frequency mutations by Duplex Sequencing. Nature Protocols, 9(11), 2586-2606. doi:10.1038/nprot.2014.170Franklin, R. M. (1966). Purification and properties of the replicative intermediate of the RNA bacteriophage R17. Proceedings of the National Academy of Sciences, 55(6), 1504-1511. doi:10.1073/pnas.55.6.1504López-Carrasco, A., Gago-Zachert, S., Mileti, G., Minoia, S., Flores, R., & Delgado, S. (2015). The transcription initiation sites of eggplant latent viroid strands map within distinct motifs in theirin vivoRNA conformations. RNA Biology, 13(1), 83-97. doi:10.1080/15476286.2015.1119365Keese, P., & Symons, R. H. (1985). Domains in viroids: evidence of intermolecular RNA rearrangements and their contribution to viroid evolution. Proceedings of the National Academy of Sciences, 82(14), 4582-4586. doi:10.1073/pnas.82.14.4582López-Carrasco, A., & Flores, R. (2016). Dissecting the secondary structure of the circular RNA of a nuclear viroid in vivo: A «naked» rod-like conformation similar but not identical to that observed in vitro. RNA Biology, 14(8), 1046-1054. doi:10.1080/15476286.2016.1223005Flores, R., Hernandez, C., de la Peña, M., Vera, A., & Daros, J.-A. (2001). Hammerhead Ribozyme Structure and Function in Plant RNA Replication. Ribonucleases - Part A, 540-552. doi:10.1016/s0076-6879(01)41175-xMartick, M., & Scott, W. G. (2006). Tertiary Contacts Distant from the Active Site Prime a Ribozyme for Catalysis. Cell, 126(2), 309-320. doi:10.1016/j.cell.2006.06.036Ruffner, D. E., Stormo, G. D., & Uhlenbeck, O. C. (1990). Sequence requirements of the hammerhead RNA self-cleavage reaction. Biochemistry, 29(47), 10695-10702. doi:10.1021/bi00499a018Flores, R., Serra, P., Minoia, S., Di Serio, F., & Navarro, B. (2012). Viroids: From Genotype to Phenotype Just Relying on RNA Sequence and Structural Motifs. Frontiers in Microbiology, 3. doi:10.3389/fmicb.2012.00217Owens, R. A., Chen, W., Hu, Y., & Hsu, Y.-H. (1995). Suppression of Potato Spindle Tuber Viroid Replication and Symptom Expression by Mutations Which Stabilize the Pathogenicity Domain. Virology, 208(2), 554-564. doi:10.1006/viro.1995.1186Takeda, R., Petrov, A. I., Leontis, N. B., & Ding, B. (2011). A Three-Dimensional RNA Motif in Potato spindle tuber viroid Mediates Trafficking from Palisade Mesophyll to Spongy Mesophyll in Nicotiana benthamiana. The Plant Cell, 23(1), 258-272. doi:10.1105/tpc.110.081414Zhong, X., Leontis, N., Qian, S., Itaya, A., Qi, Y., Boris-Lawrie, K., & Ding, B. (2006). Tertiary Structural and Functional Analyses of a Viroid RNA Motif by Isostericity Matrix and Mutagenesis Reveal Its Essential Role in Replication. Journal of Virology, 80(17), 8566-8581. doi:10.1128/jvi.00837-06Zhong, X., Tao, X., Stombaugh, J., Leontis, N., & Ding, B. (2007). Tertiary structure and function of an RNA motif required for plant vascular entry to initiate systemic trafficking. The EMBO Journal, 26(16), 3836-3846. doi:10.1038/sj.emboj.7601812Zhong, X., Archual, A. J., Amin, A. A., & Ding, B. (2008). A Genomic Map of Viroid RNA Motifs Critical for Replication and Systemic Trafficking. The Plant Cell, 20(1), 35-47. doi:10.1105/tpc.107.056606Thomas, M. J., Platas, A. A., & Hawley, D. K. (1998). Transcriptional Fidelity and Proofreading by RNA Polymerase II. Cell, 93(4), 627-637. doi:10.1016/s0092-8674(00)81191-5Gout, J.-F., Thomas, W. K., Smith, Z., Okamoto, K., & Lynch, M. (2013). Large-scale detection of in vivo transcription errors. Proceedings of the National Academy of Sciences, 110(46), 18584-18589. doi:10.1073/pnas.1309843110Hedtke, B. (1997). Mitochondrial and Chloroplast Phage-Type RNA Polymerases in Arabidopsis. Science, 277(5327), 809-811. doi:10.1126/science.277.5327.809Lerbs-Mache, S. (1993). The 110-kDa polypeptide of spinach plastid DNA-dependent RNA polymerase: single-subunit enzyme or catalytic core of multimeric enzyme complexes? Proceedings of the National Academy of Sciences, 90(12), 5509-5513. doi:10.1073/pnas.90.12.5509Oldenkott, B., Yamaguchi, K., Tsuji-Tsukinoki, S., Knie, N., & Knoop, V. (2014). Chloroplast RNA editing going extreme: more than 3400 events of C-to-U editing in the chloroplast transcriptome of the lycophyteSelaginella uncinata. RNA, 20(10), 1499-1506. doi:10.1261/rna.045575.114Codoñer, F. M., Darós, J.-A., Solé, R. V., & Elena, S. F. (2006). The Fittest versus the Flattest: Experimental Confirmation of the Quasispecies Effect with Subviral Pathogens. PLoS Pathogens, 2(12), e136. doi:10.1371/journal.ppat.0020136Eigen, M. (1971). Selforganization of matter and the evolution of biological macromolecules. Die Naturwissenschaften, 58(10), 465-523. doi:10.1007/bf00623322Lynch, M. (2011). The Lower Bound to the Evolution of Mutation Rates. Genome Biology and Evolution, 3, 1107-1118. doi:10.1093/gbe/evr066Bradwell, K., Combe, M., Domingo-Calap, P., & Sanjuán, R. (2013). Correlation Between Mutation Rate and Genome Size in Riboviruses: Mutation Rate of Bacteriophage Qβ. Genetics, 195(1), 243-251. doi:10.1534/genetics.113.154963Drake, J. W. (1991). A constant rate of spontaneous mutation in DNA-based microbes. Proceedings of the National Academy of Sciences, 88(16), 7160-7164. doi:10.1073/pnas.88.16.7160Schmitt, M. W., Kennedy, S. R., Salk, J. J., Fox, E. J., Hiatt, J. B., & Loeb, L. A. (2012). Detection of ultra-rare mutations by next-generation sequencing. Proceedings of the National Academy of Sciences, 109(36), 14508-14513. doi:10.1073/pnas.120871510

Antibody-Mediated Growth Inhibition of Plasmodium falciparum: Relationship to Age and Protection from Parasitemia in Kenyan Children and Adults

BACKGROUND: Antibodies that impair Plasmodium falciparum merozoite invasion and intraerythrocytic development are one of several mechanisms that mediate naturally acquired immunity to malaria. Attempts to correlate anti-malaria antibodies with risk of infection and morbidity have yielded inconsistent results. Growth inhibition assays (GIA) offer a convenient method to quantify functional antibody activity against blood stage malaria. METHODS: A treatment-time-to-infection study was conducted over 12-weeks in a malaria holoendemic area of Kenya. Plasma collected from healthy individuals (98 children and 99 adults) before artemether-lumefantrine treatment was tested by GIA in three separate laboratories. RESULTS: Median GIA levels varied with P. falciparum line (D10, 8.8%; 3D7, 34.9%; FVO, 51.4% inhibition). The magnitude of growth inhibition decreased with age in all P. falciparum lines tested with the highest median levels among children \u3c4 years compared to adults (e.g. 3D7, 45.4% vs. 30.0% respectively, p = 0.0003). Time-to-infection measured by weekly blood smears was significantly associated with level of GIA controlling for age. Upper quartile inhibition activity was associated with less risk of infection compared to individuals with lower levels (e.g. 3D7, hazard ratio = 1.535, 95% CI = 1.012-2.329; p = 0.0438). Various GIA methodologies had little effect on measured parasite growth inhibition. CONCLUSION: Plasma antibody-mediated growth inhibition of blood stage P. falciparum decreases with age in residents of a malaria holoendemic area. Growth inhibition assay may be a useful surrogate of protection against infection when outcome is controlled for age

Balancing repair and tolerance of DNA damage caused by alkylating agents

Alkylating agents constitute a major class of frontline chemotherapeutic drugs that inflict cytotoxic DNA damage as their main mode of action, in addition to collateral mutagenic damage. Numerous cellular pathways, including direct DNA damage reversal, base excision repair (BER) and mismatch repair (MMR), respond to alkylation damage to defend against alkylation-induced cell death or mutation. However, maintaining a proper balance of activity both within and between these pathways is crucial for a favourable response of an organism to alkylating agents. Furthermore, the response of an individual to alkylating agents can vary considerably from tissue to tissue and from person to person, pointing to genetic and epigenetic mechanisms that modulate alkylating agent toxicity