Social movements rely in large measure on networked communication technologies to organize and disseminate information relating to the movements’ objectives. In this work we seek to understand how the goals and needs of a protest movement are reflected in the geographic patterns of its communication network, and how these patterns differ from those of stable political communication. To this end, we examine an online communication network reconstructed from over 600,000 tweets from a thirty-six week period covering the birth and maturation of the American anticapitalist movement, Occupy Wall Street. We find that, compared to a network of stable domestic political communication, the Occupy Wall Street network exhibits higher levels of locality and a hub and spoke structure, in which the majority of non-local attention is allocated to high-profile locations such as New York, California, and Washington D.C. Moreover, we observe that information flows across state boundaries are more likely to contain framing language and references to the media, while communication among individuals in the same state is more likely to reference protest action and specific places and times. Tying these results to social movement theory, we propose that these features reflect the movement’s efforts to mobilize resources at the local level and to develop narrative frames that reinforce collective purpose at the national level. One of the most prominent American political movements of the past thirty years, Occupy Wall Street (‘Occupy’) is remarkable in the extent to which social media played a central role in its development and organization The organizing forces underlying successful social movements have been studied extensively by sociologists and political scientists Here we study Occupy Wall Street, a social movement focused on issues relating to the uneven distribution of wealth, social inequality, corporate greed, and the regulation of major financial institutions. Since the first protest on September 17Social media have played a prominent role in facilitating communication and coordination throughout the development of the Occupy Wall Street movement. For example, the first call to action in the Canadian anticapitalist magazine ‘AdBusters’ used the Twitter ‘hashtag’ #occupywallstreet as one of just ten words featured in a full-page ad. Ever since, the Twitter platform has been used extensively by movement participants In this work, we seek to understand the relationship between the geospatial dimensions of social movement communication networks and the organizational pressures facing such movements. To accomplish this, we use a state-of-the-art location inference technique to model relationships among users as a weighted directed network of communication flows between states, in which the weight of each edge corresponds to the volume of traffic between pairs of locations. Using this framework we investigate three distinct relationships: attention allocation and proximity to on-the-ground events, resource mobilization and localized information sharing, and the role of collective framing in long-distance communication.With respect to the issue of attention allocation, we find that compared to stable domestic political communication the Occupy Wall Street movement exhibits very high levels of geographic concentration, with users in New York, California, and Washington D.C. producing more than half of all retweeted content. Aside from these hubs, however, we find that the appeal of content relating to Occupy Wall Street has a disproportionately local audience. With extended, high profile encampments and large-scale protest action playing central roles in the Occupy movement, we propose that this structural feature reflects the importance of mobilizing human resources at the local level.Finally, we report on evidence indicating that the content of communication at the national level is distinct from the content of communication among users in the same state. Comparing intrastate versus interstate communication, we find that the terms most overrepresented in interstate communication relate to the movement’s core framing language and the news media, while the terms most overrepresented in local communication reference physical places, protest action, and specific times. These results support the hypothesis that local-level communication activity is driven by the challenge of resource mobilization, while long-distance communication is more strongly associated with collective framing processes.tweets, and interact with one another in a variety of ways. Communication on Twitter is characterized by directed, non-reciprocal social links that allow users to subscribe to the stream of content produced by another user. The content produced by every user an individual follows is aggregated into a single streaming feed, from which an individual can selectively rebroadcast content to his or her followers by choosing to retweet it. In this way, a retweet serves to broaden the potential audience of a piece of content, and signifies that information has been transmitted between two individuals. Hashtags, short tokens prepended with a pound sign (e.g. #taxes or #obama), constitute another important feature of the platform, and allow the content produced by many individuals to be aggregated into a custom, topic-specific stream including all tweets containing a given token.Twitter is a popular social networking and microblogging site extensively explored in recent literature The analysis described in this article relies on data collected from the Twitter ‘gardenhose’ streaming API between July To isolate a representative sample of Occupy Wall Street content we flagged for collection any tweet containing hashtags associated with the Occupy movement, including #ows and #occupy{*} . To provide a baseline against which to compare our observations, we also extracted content originating from the two most popular communication channels associated with stable domestic political communication, #tcot (Top Conservatives on Twitter) and #p2 (Progressives 2.0). In total, this sampling procedure produced 1,522,415 tweets associated with Occupy Wall Street and 825,262 tweets associated with domestic political communication. As this analysis is concerned primarily with information spreading processes we consider only retweet events from this corpus, resulting in 676,369 retweets among 257,657 users associated with Occupy Wall Street, and 259,703 retweets among 68,049 users associated with stable domestic political communication. Henceforth, we consider these corpora to constitute representative samples of retweet interactions among users participating in the streams of content associated with the Occupy Wall Street movement and stable domestic political communication in the United States.To facilitate a geospatial analysis of communication activity associated with these content streams we require a high quality method to infer individual users’ locations. To accomplish this, we rely on self-reported location strings and the services of a commercial geocoding API. This technique, popularized in work by Onnela et al. A caveat to this technique, however, is that it relies on raw text generated by a broad swath of the Twitter population, and so we find geographically meaningless location descriptors included in the dataset. To address this issue we rely on an extensive hand-curated blacklist of popular non-geographical responses such as ‘everywhere’ and ‘the dance floor’. To produce this list we sorted all location strings by popularity and reviewed the thousand most popular strings manually, blacklisting those that did not correspond to geographically meaningful entities. Drawn from a long tailed distribution, 53% of all tweets in the data set are associated with a location among the 1,000 most popular responses, with 27% of all tweets containing one of the top hundred location strings. From this set of one thousand we blacklisted 161 non-location strings, corresponding to 6% of the tweets associated with the 1,000 most popular responses.To improve recall in the presence of novel input, we used a modified version of the Ratcliff-Obershelp algorithm From among the remaining responses we submitted location strings to the Bing.com geocoding API, which returns a best-guess estimate for the corresponding physical coordinates. This output is hierarchically formatted to describe the finest level of geographic resolution available. For example, if a user reports ‘Logan Square, Chicago’ as his or her location, the Bing API will return information about the likely zip code, city, state and country associated with that location. However, if the user reports only ‘USA,’ the information provided by the API describes only a country-level guess as to the user’s location. Owing to decreased coverage at the city-level and the proportionately few users associated with each individual city, we utilize the state-level location estimates for the geospatial components of this analysis.In total, 68.4% of Occupy Wall Street users reported location strings, and from these we were able to obtain geolocation estimates for 55.7% of these accounts. Among this set of users, 60% of the resulting geolocation estimates included state-level metadata. Response rates were somewhat diminished for users associated with the stream of domestic political communication, with 36% of individuals reporting free-text location strings. Using the procedure described above, we were able to obtain geolocation estimates for 29.3% of all users in the domestic political communication stream, 82.4% of which contained state-level metadata.One of our goals is to establish a coarse-grained geographic profile for communication activity associated with the Occupy Wall Street movement. Formally, for each stream we define an activity distribution across states as, In addition to the distribution of activity across individual states we examine the information sharing relationships among users in different locations. To accomplish this, we rely on a network representation to characterize the flow of information on Twitter. Taking users as nodes, we define a weighted directed network in which an edge with weight Combining the user-level geocode metadata previously described with the network representation defined here we can induce another network describing the volume of communication between users in each state. In this network, nodes represent states, and weighted directed edges are drawn among them. The weight of the edge from interstate tweets connect pairs of users in different states, and intrastate tweets connect users in the same state. We compute the probability of observing a token, Finally, we wish to investigate whether the content of tweets with different geospatial properties serve distinct communication functions. To accomplish this, we segregate Occupy Wall Street tweets into two classes: We also study the ratio of content production to content consumption by locale. Geographic Profile both networks are highly dense, with edges spanning most pairs of states. To address this issue we utilize a technique known as multiscale backbone extraction To highlight the effect of this geospatial concentration on communication flows between states it is instructive to visualize the structure of these networks. However, owing to the geographic aggregation process outlined in section Applying this technique to both networks reveals a communication backbone for the Occupy network that exhibits the highly concentrated hub and spoke structure described above. In To study the relationship between geography, resource mobilization, and collective framing, we focus on the content of tweets flowing within and between states. Restricting our analysis to tokens that account for at least 0.1% of both the intrastate and interstate tweet text, The analysis of interstate connectivity patterns reveals that, relative to stable domestic political communication, the Occupy network has a highly localized geospatial structure, with a disproportionately large amount of traffic being produced and consumed by users in the same state. We propose that this phenomenon may be related to the issue of resource mobilization, that is, the process whereby any social movement must marshall resources such as money, infrastructure and human capital to further the goals of the movement. In the case of Occupy Wall Street, such resources are often quite tangible, and include not only tents and food, but also the participants required to facilitate large-scale protest action and extended encampments in cities across the country. In this light, it is easy to understand why such a disproportionately large fraction of attention is allocated to communication at the local level.With respect to the finding that the majority of widely rebroadcast content is produced by users in a small number of high profile locations, we observe that these states represent sites of major encampment and decision making activity. Despite the fact that all users can contribute equally to the Occupy stream, it appears that proximity to events on the ground plays a major role in determining which content receives the most attention. This is in contrast to the stream of domestic political communication, in which content from users across the United States is allocated a significant share of attention. Where the stream of domestic political communication looks more like a conversation taking place at the national level, the structure of the Occupy stream is more akin to a broadcast, with just a few locations playing the role of net content producers.Finally, we propose that interstate communication plays a significant role in the propagation of narrative imagery associated with collective framing processes, and that intrastate communication is driven more predominantly by the pressures of resource mobilization. Looking to the lists of tokens most overrepresented in each type of traffic , we findThe findings outlined in this paper dovetail nicely with established literature on social movement theory. However, statistical measures are limited in the extent to which they can accurately represent nuanced features of communication, and future work in this domain would benefit from rigorous qualitative content analysis. Moreover, there remains room to improve our understanding of how closely the structure of social media communication mirrors that of other forms of communication. For example, Mislove, et al. found that the geographical distribution of Twitter users tends to over-represent populous counties and metropolitan areas, suggesting that entire rural regions may be significantly under-represented – with similar findings holding true for ethnicity and gender as well


Acinetobacter osteomyelitis appears suppressed with extended antimicrobial drug therapy based on susceptibility patterns. Acinetobacter species have been prevalent during the 2003–2005 military operations in Iraq. Twenty-three soldiers wounded in Iraq and subsequently admitted to our facility from March 2003 to May 2004 had wound cultures positive for Acinetobacter calcoaceticus-baumannii complex. Eighteen had osteomyelitis, 2 burn infection, and 3 deep wound infection. Primary therapy for these infections was directed antimicrobial agents for an average of 6 weeks. All soldiers initially improved, regardless of the specific type of therapy. Patients were followed up to 23 months after completing therapy, and none had recurrent infection with Acinetobacter species. Despite the drug resistance that infecting organisms demonstrated in this series, a regimen of carefully selected extended antimicrobial-drug therapy appears effective for osteomyelitis caused by MDR Acinetobacter spp.War wound infection and osteomyelitis caused by multidrug-resistant (MDR)  Acinetobacter species. The incidence of bacteremia at military medical facilities caused by Acinetobacter baumannii has also increased  in San Antonio, Texas. This tertiary military medical center serves a population of active-duty and retired soldiers and their dependents along with a limited number of civilian trauma patients admitted from the local area. The hospital was operating at an average capacity of 175 beds during the study period. This facility also houses the US Army's Institute of Surgical Research, which treats both active-duty and civilian trauma patients with burn injuries. Data collection for this case series was completed under a study protocol approved by BAMC's Department of Clinical Investigation Institutional Review Board.Acinetobacter-positive cultures were then compared to all active-duty soldiers admitted to our facility. A soldier was considered for inclusion if he had an Acinetobacter-positive culture and had been deployed to Iraq or Afghanistan and had an admission diagnosis of injury (ICD codes 800.0–900.0). Similarly, hospital admission and laboratory data were reviewed for the 14 months before the study period to define the incidence of Acinetobacter infection in hospitalized, active-duty soldiers before the onset of military action in Iraq.All wound, sputum, urine, and blood culture results completed at our hospital from March 1, 2003, to May 31, 2004, were reviewed. Those patients who had Acinetobacter contiguous focus osteomyelitis or wound infection are included in this series. Cases were defined as osteomyelitis if bone tissue collected during surgical procedures  was positive for Acinetobacter spp. on routine culture   . On occaMO, USA) . ColistiMO, USA) .Acinetobacter spp. isolated at the original site of infection after completing an antimicrobial drug treatment course for the initial infection; secondary infection was defined as infection with a different organism at the same site as the initial Acinetobacter infection.Patients were evaluated for recurrence of infection. Many patients underwent subsequent reconstructive surgeries, and the bone tissue was sent for culture. Definitions of recurrent infection followed the previously described criteria for the case definitions with the following additions: recurrent infection was defined as having Acinetobacter species isolated and antimicrobial drug susceptibilities. Patients were also interviewed either in person or by telephone to confirm mechanism of injury, length of antimicrobial drug treatment course, recurrence of infection, subsequent hospital admissions, and clinical outcome of the sustained injury and infection . Follow-up was defined as the time from completing the initial antimicrobial treatment course to the date of the study interview.Both electronic and paper charts of all patients who met case definition criteria were retrospectively reviewed for demographic, diagnostic, and treatment data. Laboratory results were reviewed for Acinetobacter spp. During the same period, 237 active-duty patients were admitted to our facility with the admission diagnosis of injury  represented clinical infection; the remaining 18 represented colonization with Acinetobacter. Of those patients with cultures that represented clinical infection, 23 met the case definition for Acinetobacter osteomyelitis (Acinetobacter wound infection (Acinetobacter infection. The incidence of Acinetobacter infection during the study period represents a significant increase when compared to the control period (p<0.01 by 2-tailed Fisher exact test).From March 1, 2003, to May 31, 2004, a total of 24,114 cultures  were completed in our hospital. Of these, 145 (0.6%) were positive for f injury . Of thesmyelitis  or Acinenfection . During Acinetobacter infection was initially identified at BAMC in 15 of the 23 patients; the remainder were identified at a previous medical center. None were initially diagnosed prior to evacuation from Iraq or Afghanistan. The median age of the patients was 26 years (range 20–48), and all but 2 were men. Patients were generally stable on admission to BAMC and did not require admission to an intensive care unit.All patients included in this series had been transferred to BAMC through the military airmobile medical evacuation system. All, excluding one, were evacuated through, and admitted for at least 1 day to, Landstuhl Army Medical Center in Landstuhl, Germany; 3 patients were admitted to a second US Army medical center before admission to BAMC. The median time from injury to admission at BAMC was 6 days ; patient no. 23 had a soft tissue wound culture positive on hospital day 8 (postinjury day 10).Patients with Acinetobacter spp.  in combination with high-dose amikacin (15–20 mg/kg daily). In a few instances, when imipenem was not active against the isolated organism, ampicillin/sulbactam or ceftazidime was used if either was active against the particular isolate . These secondary infections primarily involved other resistant nosocomial pathogens (The follow-up period was 1–23 months (mean 9 months). During this time, no athogens  and 2.Acinetobacter infection. A soft tissue infection with Acinetobacter developed in 1 soldier with a history of bullous pemphigoid. Bacteremia with Acinetobacter developed in the other soldier, who had a history of Ewing sarcoma. The latter Acinetobacter isolate was not a MDR organism and was treated with imipenem  for 14 days.During the 14 months before March 2003, only 2 active-duty soldiers had Acinetobacter in our facility. Similarly, the rate of blood, wound, or urine cultures positive for Acinetobacter species increased 3-fold during the study period as compared to the control time period (data not shown). This increase and the influx of severe extremity infection due to MDR Acinetobacter species posed considerable challenges. The foremost was determining appropriate therapy for osteomyelitis caused by MDR Acinetobacter species without institutional or historical experience to guide us. In addition, increasing prevalence of this MDR gram-negative organism in our facility mandated new infection control procedures to limit nosocomial spread. Finally, the occurrence of Acinetobacter wound infection was somewhat unexpected, and initially the reservoir for infection was unclear and generated much debate. Recent investigation by the military medical and research community suggests that these are nosocomial infections; however, their exact source remains unclear.The 23 cases observed during the study period represent a significant increase in the incidence of clinical infection with Acinetobacter infections reported in the literature reflect nosocomial Acinetobacter, as hospitalized patients are at increased risk because of severe illness or disability, extremes of age, and relative states of immunocompromise (Acinetobacter species can cause infection in any organ system, including bacteremia, pneumonia, endocarditis, meningitis, urinary tract infection, intraabdominal abscess, osteomyelitis, soft tissue infection, and surgical site infections (Acinetobacter species (Acinetobacter infection are 19%–54% (Most mpromise . Acinetofections . Data co species . Crude d 19%–54% –15. The  19%–54% ,12. A coAcinetobacter species is scant. It has been described after a hamster bite in an 8-year-old boy (Acinetobacter species but did not report details of therapy or followup (Acinetobacter isolate. Once those infected with MDR isolates demonstrated clinical improvement and normalization of inflammatory markers, antimicrobial drug therapy was discontinued without continuing long-term suppressive therapy (When these patients were first evaluated, data to guide therapeutic decisions were limited. Previous reported experience with osteomyelitis caused by -old boy  and in a-old boy . Other rfollowup ,11. Patifollowup . While o therapy  and 2.Acinetobacter osteomyelitis have occurred. The relative brevity of follow-up is a limitation of this study. The ultimate outcome for these patients will not be known for many years, as they have increased risk for recurrent infection throughout their lifetime. In addition, Acinetobacter organisms do not possess substantial inherent virulence. None of the patients in this series failed therapy, and none died because of Acinetobacter infection. Such is not the case in outbreaks among immunocompromised or intensive care patients, in whom Acinetobacter infection leads to increased mortality (During the follow-up period, no recurrent episodes of ortality –15. The Acinetobacter is an important nosocomial pathogen with multiple recent outbreaks reported (Acinetobacter in our facility led to new infection control procedures. Currently, all injured soldiers admitted to our facility returning from OIF/OEF are placed in contact isolation. Screening cultures of the axilla, groin, and any open wound are completed to assess for colonization with MDR Acinetobacter, which was identified in 18 of 151 admitted soldiers during the study period (Acinetobacter are kept in contact isolation for the duration of hospitalization. Implementation of these types of infection control procedures has limited nosocomial spread in previously reported outbreaks (MDR reported –22. It hreported ,24, whicy period . If all utbreaks ,22, whicAcinetobacter, and that this colonization was obtained from the environment. This hypothesis was based on 2 facts. First, these organisms are ubiquitous in the environment (Acinetobacter spp. had previously been described as common pathogens in war wounds (Acinetobacter infections. Investigation into the cause of these infections is ongoing, but the source is unlikely to be environmental. Multiple follow-up soil samples have not yielded Acinetobacter, yet it has been recovered from environmental cultures within field medical facilities. The final outcome of this investigation is pending further analysis.As previously noted, we initially suspected that colonized soldiers themselves were the reservoir for MDR ironment ,25, and r wounds , supportAcinetobacter infection, including osteomyelitis, can be successfully treated with appropriate surgical debridement, directed antimicrobial drug therapy, and careful follow-up. Our patients responded to this multifaceted approach, although their final outcome will not be determined for several years. These patients continue to be followed for recurrence of MDR Acinetobacter infection. Clearly, guided therapy based on antimicrobial drug susceptibility leads to suppression of recurrent infection up to 23 months. Most of the patients in this series did not receive extended continuation therapy with oral antimicrobial agents; whether such therapy would provide added benefit is unclear. However, few antimicrobial drug options are currently available, with none soon to be released, to treat infections caused by resistant gram-negative organisms. Increasing prevalence of these types of infections highlights the necessity for newer antimicrobial agents with activity against these organisms.Data from this case series demonstrate that highly resistant


Scandinavian Journal of Primary Health Care is a modern medical journal dedicated to publishing family medicine research. The journal seeks to be among the leading similar journals in the world. One of the great developments within publishing scientific papers has been the use of electronic media where it is possible to make an early and fast publication of new knowledge. It has become more and more evident that new knowledge should be easily accessible and available at a very early stage to facilitate early implementation of important medical knowledge. This implies an open and easy access to papers published in a medical journal.Increasing medical knowledge demonstrates implications for not only clinical professionals, but also for the organisation and the performance of the health care system. This is seen e.g. by the growing amount of health services research within family medicine. Thus, patient-oriented clinical research, population-based epidemiological research and health care oriented health services research are now in high demand from clinicians, decision makers and researchers.Scandinavian Journal of Primary Health Care plays an important role in disseminating such knowledge. Therefore, it is highly prioritised to ensure that research supported by public funding is also publicly available. During a number of years, Scandinavian Journal of Primary Health Care has provided open access to the papers published in the journal. All papers are freely available online and through PubMed. The Nordic Federation of General Practice is proud of such a substantial contribution and is now taking a further step in that development.From January 2014, after 31 paper volumes since 1983, Scandinavian Journal of Primary Health Care will not be printed on paper. The journal will become an online-only medical journal benefiting from all the possibilities inherited with that. This also implies that there will not be a paper version of the Scandinavian Journal of Primary Health Care in your mailbox anymore. You now have to make sure that you, if not already, have signed up for an e-mail version of the journal using the link below.With this change a fantastic and important era with a paper journal from the Nordic countries has ended. Nevertheless, the Scandinavian Journal of Primary Health Care will continue to develop into an even more important journal within family medicine and try its best to support patient care on a knowledge-based platform. This is only possible as the journal receives such a huge amount of relevant and well-done research.As an online-only journal, Scandinavian Journal of Primary Health Care, will be allowed to publish in colour, publish additional online material like questionnaires and to accept longer manuscripts, if relevant. The layout of the papers will change slightly during 2014, and we look forward to presenting the new design. Lastly, the new online structure will give us all the full advantages of using our website and the social media.www.sjphc.org.Open access makes academic research in primary care freely available online. However, this also means that the journal has increased author fees. The author fees will be one for members of one of the Nordic societies for general practice, and one fee for non-members. For more details, please refer to the journal's website at


Journal of the World Allergy Organization (WAO) was officially launched; the first issue of WAO Journal appeared in January 2008. In several aspects, this was a major move and a great decision for WAO: After 20 years with Allergy Clinical Immunology International --Journal of World Allergy Organization (ACII-JWAO), the board of directors decided to open totally new doors and launch a new electronic-only journal. We can reach 30,000 practicing allergists worldwide via e-mail, allowing a much higher degree of flexibility and actuality. On the other hand, many of our readers still like paper and have to get used to the new electronic style. We believe, however, that this is the future of scientific communication and interchange! Both for WAO and for the publisher, it is an experiment; there are still just few electronic-only journals as official organs of national or international specialty societies. However, we are confident that WAO is on the road to success.One year ago at the World Allergy Congress in Bangkok, the new WAO covered large parts of the broad spectrum of the interdisciplinary field of allergy, both in research and clinics.With approximately 40 articles published in this first year--most of them of highest quality--WAO is in progress; under the new president, Walter Canonica--in the succession of Mike Kaliner, Carlos Baena Cagnani, Allen Kaplan, Gunnar Johansson, and so many famous allergists--the organization has become the leading force in international allergology, achieving much more than organizing a large congress every other year. WAO is the platform for everybody who wants to contribute to advance excellence in patient care, research, and education in the field of allergy and clinical immunology.WAO is in progress, but also allergy is rapidly developing.Not only The bad news first. There is still an increasing prevalence of many allergic diseases all over the world, also in countries where these diseases were rather rare 20 years ago. At the same time, allergic diseases become more and more complex and difficult to diagnose and treat; furthermore, there seems to be an age shift with not only children and young adults affected but more and more adults and elderly persons suffering from severe allergies.Allergen-specific immunotherapy (ASIT) has considerably improved in quality and efficacy and safety; however, it is applicable only to a small number of allergic patients. So many people are suffering from allergies, where ASIT does not exist or is not available.There are also good news. As rapidly as allergy prevalence was growing, the progress in allergy research is going on--we just want to mention the discovery of gene loci closely associated with allergic diseases as the cytokine cluster on chromosome 5, the ADAM 33 for bronchial hyperreactivity or the filaggrin mutations for atopic eczema. Progress has been made in ASIT with new extracts, adjuvants, and route of application.There is also great progress in education, not only for medical students and doctors but also for patients and patient organizations. Educational programs have been developed successfully--some of them with proven efficacy in randomized prospective trials--for asthma and eczema and are being started for anaphylaxis. On the basis of this improved education of doctors, better clinical care for allergic individuals has been achieved in many countries of the world; yet, there is still a lot to do!WAO Journal considers itself to be one tool in the big effort to improve the lives of allergic patients all over the world.WAO board of directors and the staff in Milwaukee  but also the people from the publisher , the regional associate editors, and the members of the editorial board who have helped to shape WAO, and last but not least the authors who have submitted excellent papers and the reviewers who have helped to make them even better!At the end of this year, it is time to thank so many people involved in this undertaking, first of all, not only the With all our best wishes for the coming holidays and a happy, healthy, and peaceful New Year 2009!Johannes Ring(Editor in Chief)Lanny Rosenwasser(Co-editor in Chief)


The Journal of Therapeutic Ultrasound has been established to provide an open access, online venue for the exponentially growing body of work in biomedical ultrasound therapy. Journal of Therapeutic Ultrasound (JTU), a newly launched, online, open-access journal designed to accelerate the development of focused ultrasound and its adoption in the clinic.Welcome to the n = 2 exp((t - 1970)/6), with coefficient of determination R2 = 0.965 and time constant τ = 6 years. In 2011, therapeutic ultrasound received attention from the popular press; following a presentation at TEDMED 2011 by Dr. Yoav Medan [Time Magazine named focused ultrasound therapy as one of the 50 Best Inventions of 2011 in its 2011 November 28 issue [Biomedical therapy was among the earliest applications of ultrasound, preceding solid state electronics and inexpensive computers by decades. However, there was insufficient commercialization for therapeutic ultrasound devices to be grandfathered into the Medical Device Amendments of 1976 to the United States Federal Food, Drug, and Cosmetic Act . In the av Medan , Time MaAdoption of new International Electrotechnical Commission standards  by regulatory agencies such as the United States Food and Drug Administration (FDA), the European Commission, the Japanese Pharmaceuticals and Medical Device Agency (PMDA), and the Chinese State Food and Drug Administration (SFDA) will enable more rapid approval of devices and, therefore, more clinical applications. Thus, the exponential growth is likely to continue with a predicted output of 3,600 articles by 2015.In order to serve this growing demand, this journal was originally proposed by Dr. Neal Kassell, Chairman of the Focused Ultrasound Foundation, in collaboration with Dr. Lawrence Crum, Past President of the International Society for Therapeutic Ultrasound (ISTU). JTU serves as the official journal of these two organizations. The 26 members of its editorial board represent 10 countries.The Journal accepts research articles, case reports, reviews, meeting reports, and study protocols, along with supplemental materials. Appropriate topics include translational and clinical research in all areas of therapeutic ultrasound, including stimulation, inhibition, destruction, or modification of tissue function or structure via focused ultrasound.Peer review follows the traditional closed model with a minimum of two reviewers. Authors are encouraged to carefully follow reporting standards for ultrasound dose  and to fAs an online journal, JTU offers authors unlimited color images and support for additional materials such as audio and video files. Another advantage is rapid publication following acceptance after successful completion of peer review.Open access means that authors retain full rights to their articles through the Creative Commons license and that articles will reach a wide audience including developing countries and mainstream media. Articles will be deposited with PubMed Central upon publication without the 6- to 12-month delay which is common among restricted access journals.Author fees are waived through 2014 through support provided by the Focused Ultrasound Foundation.The Journal is intended to reach scientists and clinical practitioners interested in broadening their knowledge in the field of therapeutic ultrasound, including MR-guided and ultrasound-guided focused ultrasound surgery, high intensity focused ultrasound, and non-ablative ultrasound therapies. By reaching audiences around the world, it will play a key role in advancing clinical applications of therapeutic ultrasound.


Clostridium thermocellum is a major candidate for bioethanol production via consolidated bioprocessing. However, the low ethanol tolerance of the organism dramatically impedes its usage in industry. To explore the mechanism of ethanol tolerance in this microorganism, systematic metabolomics was adopted to analyse the metabolic phenotypes of a C. thermocellum wild-type (WT) strain and an ethanol-tolerant strain cultivated without (ET0) or with (ET3) 3% (v/v) exogenous ethanol. Metabolomics analysis elucidated that the levels of numerous metabolites in different pathways were changed for the metabolic adaption of ethanol-tolerant C. thermocellum. The most interesting phenomenon was that cellodextrin was significantly more accumulated in the ethanol-tolerant strain compared with the WT strain, although cellobiose was completely consumed in both the ethanol-tolerant and wild-type strains. These results suggest that the cellodextrin synthesis was active, which might be a potential mechanism for stress resistance. Moreover, the overflow of many intermediate metabolites, which indicates the metabolic imbalance, in the ET0 cultivation was more significant than in the WT and ET3 cultivations. This indicates that the metabolic balance of the ethanol-tolerant strain was adapted better to the condition of ethanol stress. This study provides additional insight into the mechanism of ethanol tolerance and is valuable for further metabolic engineering aimed at higher bioethanol production. Clostridium thermocellum, a gram-positive thermophilic anaerobic bacterium, has been proposed as a potential candidate microorganism for bioethanol CBP production due to its high efficiency of cellulose degradation and direct production of ethanol C. thermocellum has been hampered because of its low hemicellulose utilisation, low ethanol productivity and titre, and low ethanol tolerance C. thermocellumC. thermocellum is still one of the major bottlenecks of its bioethanol industrialisation.Bioethanol produced from lignocellulosic biomass is a prospective and attractive substitute for petroleum-based liquid fuels as a sustainable and renewable source of energy C. thermocellum. Some ethanol tolerant (ET) strains have been obtained by gradual ethanol-adaption growth, genetic engineering, and chemical or UV mutagenesis C. thermocellum has been studied via analysis of membrane composition and structure C. thermocellum ethanol-tolerant strains, as well as fatty acid composition which have resulted in an increase of membrane rigidity, have been observed C. thermocellum ET strains revealed a large number of mutation sites, and a mutation in an alcohol dehydrogenase-encoding gene appears to confer most of the ET phenotypes C. thermocellum grow slower than the wild-type (WT) strain, and the yield of ethanol in ET strains is often lower than that in the WT strain C. thermocellum suggest that the metabolism in ET strains is significantly changed compared with the WT strain.Many efforts have been made to understand the ethanol tolerance mechanism and to improve the ethanol tolerance of C. thermocellum more deeply, we adopted systematic metabolomics to compare the intracellular and extracellular polar-/fatty-phase metabolites in C. thermocellum WT and ET strains in the absence and presence of 3% (v/v) exogenous ethanol  using nuclear magnetic resonance (NMR), gas chromatography-mass spectroscopy (GC-MS), and ion chromatography (IC). Significant differences in the levels of many metabolites were observed in our analysis, which sheds new light on the mechanism of ethanol tolerance of C. thermocellum and provides new clues and strategies for metabolic and fermentation engineering to improve the ethanol tolerance and production of C. thermocellum.The “-omics” technologies, such as genomic, transcriptomic, proteomic, and metabolomic profiling, can provide deep insight into the molecular mechanisms of certain phenomena or responses 2HPO4·3H2O, NaH2PO4·2H2O and nonadecanoic acid  were purchased from Guoyao Chemical Co. Ltd.  and used without further treatments. D2O (99.9% in D) and 4,4-dimethyl-4-silapentane-1-sulfonic acid (DSS) were purchased from Cambridge Isotope Laboratories . Amino acid standards for IC analysis were purchased from AccuStandard Inc. . Carbohydrate and organic acid standards for IC analysis were purchased from Sigma-Aldrich . Cation standards  for IC analysis were purchased from the Shanghai Institute of Measurement and Testing Technology .Sodium chloride, KC. thermocellum ATCC 35609 were kindly provided by Prof. Jian Xu . The culture media were derived from GS-2 media 2PO4 1.0, K2HPO4·3H2O 5.0, Urea 1.0, MgCl2·6H2O 2.5, CaCl2·2H2O 0.05, FeSO4·7H2O 0.00125, cysteine hydrochloride 3.0, cellobiose 10.0, MOPS 6.0, yeast extract 10.0, Na3C6HO7·2H2O 3, and redox indicator resazurin 0.002, pH 7.6). All media were prepared in an anaerobic cabinet with an atmosphere of mixed gases , and the cultivations were conducted in 1000 mL anaerobic bottles with 300 mL, 400 mL and 600 mL of fresh medium for the WT, ET0 and ET3 cultivations, respectively. All cultures were grown at 60°C. The biomass was determined by optical density (OD600) and dry cell weight (DCW) in triplicate.The wild-type and ethanol-tolerant strains of 2HPO4, and 2 mM KH2PO4) 3 times.The cultivations were stopped at the late logarithmic phase by cooling in an ice-water bath for a half hour to quench metabolic activity, and the metabolites in the samples before and after quenching were checked by NMR to ensure there was no difference . The celThe intracellular polar metabolites were extracted using a boiling ethanol method 2O together with 100 µL of phosphate buffer  containing 10% D2O and 0.02 mM DSS. The mixture was centrifuged at 4°C , and the obtained supernatant was transferred into a 5-mm NMR tube for NMR analysis. Two blanks were always prepared in parallel during extraction. All 1H-NMR spectra were recorded at 298 K using a Bruker 600 NMR spectrometer (600.13 MHz for 1H) equipped with a 5-mm triple resonance cryoprobe . A standard one-dimensional noesypr1d pulse sequence was used to quantify the intracellular polar metabolites. Water suppression was achieved with a weak irradiation during the recycle delay (2 s) and the mixing time (100 ms). 64 transients were collected into 32768 data points for each spectrum with a spectral width of 12 kHz. An exponential window function with a line broadening factor of 0.5 Hz was applied to all free induction decays prior to Fourier transformation. For resonance assignment purposes, two-dimensional 1H-1H TOCSY, 1H-1H COSY, 1H-13C HSQC and 1H-13C HMBC spectra were acquired. In the COSY and TOCSY experiments, 48 transients were collected into 2048 data points for each of 256 increments, and the spectral widths were 6 kHz for both dimensions. Phase-insensitive mode was used with gradient selection for the COSY experiments, whereas the MLEV-17 was employed as the spin-lock scheme in the phase-sensitive TOCSY experiment with a mixing time of 100 ms. 1H-13C HSQC and HMBC spectra were recorded using gradient selected sequences with 200 transients and 2048 data points for each of 128 increments. The spectral widths were 6 kHz for 1H and 26 kHz (HSQC) or 33 kHz (HMBC) for 13C. The data were processed into a 4096 by 2048 matrix via Fourier transformation.Approximately 40 mg of extracted powder of polar metabolites was added into 500 µL of 100% D1H-NMR spectra. These spectra were manually corrected for phase and baseline distortions using TOPSPIN , and the spectral region (δ = 0.5–9.5) was uniformly integrated into 3166 buckets with a width of 0.003 ppm (1.8 Hz) using the AMIX package . A region (δ = 4.67–4.90) was discarded to eliminate the effects of imperfect water presaturation. The spectral areas of each bucket were normalised to the internal reference (DSS). The absolute levels of the metabolites were calculated, as milligram per gram freeze-dried metabolite extracts, from the least overlapping NMR signals of the metabolites and the relevant DSS values with known concentrations. These semi-quantitative data were expressed in the form of the mean ± standard deviation and were also subjected to classical one-way ANOVA analysis using SPSS 13.0 software and a Turkey post-test (p<0.05).The quantification of the intracellular polar metabolites was obtained from analysis of the 2SO4-methanol (v/v) with an internal standard  for quantitative determination. The fatty acid methyl esters (FAMEs) were analysed with an Agilent 7890-5975 GC-MS system  equipped with a 30 mm×0.25 mm×0.25 µm capillary column (Agilent HP-INNOWAS). The oven temperature was initially 100°C and increased up to 240°C over 10 min (15°C min−1). The split ratio was 1:20, and helium was used as the carrier gas at a flow rate of 1.0 mL min−1 in constant flow mode. The ion source and quadrupole temperatures were 230°C and 150°C, respectively. The mass spectrometer was operated in electron impact mode at 70 eV with a scan range of 30–400 m/z. The injection sample volume was 1.0 µL.The total lipid in the fatty phase extracts were converted to methyl esters using 2.5 mL of 2% HThe frozen extracellular metabolite samples were thawed and filtered using a filter with a 0.22-µm pore size. Four types of extracellular targeted metabolites  were identified using an ICS-3000 system and an ICS-5000 system . The standard curves of 20 amino acids, 10 carbohydrates, 12 organic acids, and 5 cations were measured and used to quantify the corresponding extracellular metabolites. The concentrations of the metabolites in an uncultured medium were also measured as a negative control. The negative control concentrations were subtracted from the concentration of extracellular metabolites in the samples. Therefore, the extracellular metabolite contents are presented as positive or negative values, which indicate released or assimilated metabolites, respectively.0 and ET3C. thermocellum cultivations are shown in 0 and ET3 cultivations displayed longer lag phases and lower maximal biomass yields than that of WT, whereas the maximal biomass of ET3 was only around half of that of ET0. These results indicate that cell growth was inhibited by ethanol, which was proven in a previous report The growth and dry cell weight curves of the WT, ETC. thermocellum to investigate the intracellular ethanol-tolerant strain metabolic changes.Intracellular metabolome analysis, referred to as metabolic fingerprinting, can directly provide the cellular metabolic profile and metabolic changes in specific environments 0 and ET3C. thermocellum cultivations were analysed by NMR . The accumulation of cellodextrins in C. thermocellum was observed in previous studies. C. thermocellum has been demonstrated to be able of assimilating cellodextrins hydrolysed from extracellular cellulose 0C. thermocellum harboured a higher concentration of cellodextrins than the WT, and the cellodextrin level in the ET3 bacteria was similar to that in WT, although the other metabolites in the ET3 bacteria were significantly decreased in comparison with the WT, which suggests the synthesis of cellodextrins in the ET strain was more active than that in the WT stain and perhaps indicates a new metabolic regulation mechanism responded to the ethanol. To check the effect of cellodextrins in C. thermocellum, the growths of the ET strain in absence and presence of additional cellodextrins were compared  was the most significantly changed metabolite  in the ET3 cultivation was approximately one-third of that in ET0 cultivation. These results indicate that the biosynthesis of NAD, compared to the biosynthesis of NADP, was obviously more affected by ethanol. The low level of NAD could be disadvantageous for many NAD-specific enzymes that can be very important in the process of cell growth, such as alcohol dehydrogenase, although NADP is generally more important to cell growth. Thus, this result might partially explain why the co-factor specificity change from NAD to NADP of alcohol dehydrogenase could influence the ethanol tolerance as previously reported C. thermocellum.When comparing the metabolite concentrations in the ETtabolite . The levthermocellum WT, ET0 and ET3 cultivations. In total, 17 metabolites were identified and quantified by GC-MS . These results indicate that the adjustments of membrane composition under stress conditions were relatively slow compared with other metabolite changes, but some adjustments were kept in ET stains during long-term adaption. Furthermore, we observed that some fatty acids with odd carbon numbers  displayed reversed changes when comparing ET0/WT and ET3/ET0. The percentage of these fatty acids among the total fatty acids was relatively low, so these changes might have little effect on the membrane but still reflect the responses of fatty acid biosynthesis to ethanol stress.Fatty phase metabolites are generally the major components of the cell membrane, and thus the composition of fatty phase metabolites could provide important information about the membrane, such as the fluidity, which is considered to be a key factor in ethanol tolerance by GC-MS . Similar0 and ET3 cultivations by IC , which was almost completely consumed in all three types of cultivations. The biomass of the ET cultivations was much less than that of the WT cultivation  was taken up completely in the ET strain but it was not converted into biomass or ethanol. Instead, greater amount of other metabolites, including amino acids and some organic acids, were produced in the ET strain, and some intermediate metabolites were more significantly overflowed. Therefore, the metabolic balance in C. thermocellum was not optimised for ethanol production, which might partially explain why the deletion of some by-product pathways only slightly affects the ethanol production in C. thermocellumC. thermocellum are needed to obtain an engineered strain with a high ethanol yield. For example, a recent successful study reported that the introduction of an exogenous pyruvate kinase increased the ethanol yield over 3-fold in C. thermocellum with enhanced ethanol tolerance C. thermocellum WT strain. Therefore, more engineering studies, including both introducing exogenous pathways and the modification of endogenous pathways, are necessary for obtaining an industrial ethanol-producing strain of C. thermocellum.The extracellular metabolome of C. thermocellum displayed metabolic adaption in various metabolic pathways. The changes in the intracellular polar and fatty phase metabolites and extracellular-targeted metabolites indicated that the nutrient uptake, central metabolism, membrane structure, amino acid biosynthesis, and cation transport were adapted to ethanol stress. Cellodextrins were more significantly accumulated in the ethanol-tolerant strain as a potential anti-stress mechanism. The overflow of many intermediate metabolites indicated the imbalance of metabolic flow in C. thermocellum, and the ethanol-tolerant strain displayed a better adaption under the conditions of ethanol stress compared with the wild-type strain.The ethanol-tolerant strain of Figure S11H NMR spectra of the extracted intracellular polar metabolites from wild-type Clostridium thermocellum before (black) and after (red) quenching experiments.(PDF)Click here for additional data file.Figure S20 and ET3Growth (black) and dry cell weight curves (grey) of the WT, ETC. thermocellum cultivations.(PDF)Click here for additional data file.Figure S3The growth curves of ethanol-tolerant Clostridium thermocellum with and without cellodextrins.(PDF)Click here for additional data file.Table S1The NMR assignments of intracellular polar metabolites.(PDF)Click here for additional data file.Table S2The change ratio of metabolites concentrations in control experiments.(PDF)Click here for additional data file.


Annales de Parasitologie humaine et comparée, which had been created in 1923 by Emile Brumpt with the help of Maurice Langeron and Maurice Neveu-Lemaire, became Parasite, a journal dedicated to continuing scientific dissemination of French parasitologists. The Annales de Parasitologie humaine et comparée, themselves succeded to the Archives de Parasitologie created by Raphaël Blanchard in the previous century. In the first issue of Parasite, the President of the French society of Parasitology, Jean Antoine Rioux, stressed the impact of new scientific approaches, but also on the need for the integration of various currents of thought. At the same time, Wallace Peters, member of the Scientific Board of the new journal paid a warm tribute to Alain Gabriel Chabaud, who had edited the Annales de Parasitologie humaine et comparée for the previous twenty years.Twenty years ago, the French Parasitology Society bought out its publisher, thanks to the profit made during the ICOPA VII. The journal Parasite has an international standing amongst the journals indexed in parasitology. The role of the Editor-in-Chief, Jean-Marc Dumas has been also decisive, due to him being a parasitologist with training in scientific publishing . Together with his wife Gisèle Gilkes-Dumas, he had just created the Princeps publishing company that provided Parasite with logistics and rigorous management without which such an undertaking would not have occurred. Thanks to its wide range of topics, Parasite was and is able to disseminate the work of parasitologists worldwide: this editorial is an opportunity to thank all the contributors and to encourage them to continue this partnership.Keeping a parasitology journal alive until today is the result of strong and skillful team-work. This united team included the board of French Society of Parasitology, and in addition a Scientific Board made up of prominent French and foreign parasitologists, and a high level Editorial Board. Over the years, these different boards were supplemented with new competences when necessary. Their effectiveness has guaranteed the quality of published manuscripts and now Parasite changes, but continues to serve the parasitology research community! Scientific publishing is currently experiencing the great upheaval of the online publication and free access. Over the last two years Parasite has followed this trend without abandoning the paper edition. Adapting to these new conditions of publication justifies both a change of publisher and editorial team. However, the spirit of the journal continues and its fascination for “this object of natural history that is a parasite” described so eloquently by Jean Antoine Rioux’s editorial twenty years ago. In closing, I wish a great success to the new editorial team of Parasite.The journal


Construction of artificial polyepitope antigens is one of the most promising strategies for developing more efficient and safer vaccines evoking T-cell immune responses. Epitope rearrangements and utilization of certain spacer sequences have been proven to greatly influence the immunogenicity of polyepitope constructs. However, despite numerous efforts towards constructing and evaluating artificial polyepitope immunogens as well as despite numerous computational methods elaborated to date for predicting T-cell epitopes, peptides binding to TAP and for antigen processing prediction, only a few computational tools were currently developed for rational design of polyepitope antigens.Here we present a PolyCTLDesigner program that is intended for constructing polyepitope immunogens. Given a set of either known or predicted T-cell epitopes the program selects N-terminal flanking sequences for each epitope to optimize its binding to TAP (if necessary) and joins resulting oligopeptides into a polyepitope in a way providing efficient liberation of potential epitopes by proteasomal and/or immunoproteasomal processing. And it also tries to minimize the number of non-target junctional epitopes resulting from artificial juxtaposition of target epitopes within the polyepitope. For constructing polyepitopes, PolyCTLDesigner utilizes known amino acid patterns of TAP-binding and proteasomal/immunoproteasomal cleavage specificity together with genetic algorithm and graph theory approaches. The program was implemented using Python programming language and it can be used either interactively or through scripting, which allows users familiar with Python to create custom pipelines.http://tepredict.sourceforge.net/PolyCTLDesigner.html.The developed software realizes a rational approach to designing poly-CTL-epitope antigens and can be used to develop new candidate polyepitope vaccines. The current version of PolyCTLDesigner is integrated with our TEpredict program for predicting T-cell epitopes, and thus it can be used not only for constructing the polyepitope antigens based on preselected sets of T-cell epitopes, but also for predicting cytotoxic and helper T-cell epitopes within selected protein antigens. PolyCTLDesigner is freely available from the project’s web site:  One of the most promising approaches to designing more efficient and safer vaccines is construction of artificial polyepitope antigens -6. TheirBoth interaction of peptides with MHC molecules and peptides binding to TAP complex are sufficiently specific for certain amino acid patterns. Proteasomal and immunoproteasomal cleavage sites are also to a considerable degree determined by the amino acid sequences of antigens and degenerate amino acid motifs that determine the efficiency of proteasomal cleavage sites are currently known ,31 as weIt has been shown that longer peptides transported into the endoplasmic reticulum (ER) undergo N-terminal trimming by ER aminopeptidases (ERAPs) to allow them to bind MHC class I molecules , and thaThe goal of this work was to develop a program intended for rational design of polyepitope T-cell antigens with a special focus on optimizing their immunogenicity via selecting amino acid spacer sequences for each pair of epitopes and choosing the optimal ordering of the epitopes within the polyepitope.A program named PolyCTLDesigner was developed. Given a set of either known or predicted CTL epitopes, PolyCTLDesigner predicts affinity of their binding to TAP and then N-termini of inefficient binders are extended with certain flanking residues using the model created by Peters et al. , implyinThen all possible pairs of obtained oligopeptides are produced and PolyCTLDesigner predicts the proteasomal and/or immunoproteasomal cleavage sites using the models developed by Toes et al. . AccordiW is the weight (rank) of spacer sequence ss between the epitopes pep1 and pep2; rankHLA is the rank of non-target junctional epitope predicted to be the most efficient binder for HLA class I allele HLA; freqHLA is the genotypic frequency of that allele within the population of interest  is the length of spacer ss; rankpr corresponds to the rank of proteasomal cleavage site predicted at the pep1 C-terminus ; rankimpr is the rank of immunoproteasomal cleavage site; rankHLA value; Neps is the number of predicted junctional epitopes and NHLA is the number of HLA alleles predicted to bind non-target epitopes with sufficient affinity , the value of 2 corresponds to high affinity (7.3 ≤ pIC50 < 8.3) and 3 corresponds to the highest affinity . Thus the optimal spacer sequence should have the least weight.where om dbMHC ); len and edges corresponding to allowed epitope matchings. Each edge has two parameters: the optimal spacer sequence and its weight which was calculated by the ranking function described above. The constructed weighted digraph is in turn transformed into a complete one by adding edges corresponding to disallowed epitope matchings; their weights are set to 5000 while the weights of allowed epitope matchings usually don’t exceed 10. The sequence of desired polyepitope antigen can be determined as the least weighted complete simple path in the constructed weighted digraph, and as one can see this task is related to the travelling salesman problem (TSP). To find optimized sequence of polyepitope antigen PolyCTLDesigner uses either greedy nearest neighbor approach (only in the case of a nondegenerate spacer sequence), or genetic algorithm-based TSP-solver implemented in PyEvolve library . The maiBuilding the graph is the most time consuming step and for a set of 40–50 peptides it can take about 6–8 hours to be completed on typical desktop personal computer. However in future we plan to implement parallelized algorithm to reduce time consumption.To illustrate the importance of poly-CTL-epitope optimization we performed a small theoretical analysis: six well-defined HLA-A*02:01-restricted HIV-1 CTL epitopes were used to produce artificial polyepitopes using our PolyCTLDesigner program. It was found that probability of selecting an optimal epitopes permutation at random was less than 0.00139 and only 17% of all possible polyepitope constructs did not contain inefficient proteasomal cleavage sites between target CTL epitopes. Besides, the choice of spacer sequences can have a great impact on proteasomal cleavage efficiency, especially for certain peptides. The detailed description of the study and its results can be found in Additional file In addition, PolyCTLDesigner is also able to assist in constructing polyepitope fragments containing T-helper epitopes. Currently T-helper epitopes can be predicted with ProPred models  : platform-independentProgramming language: PythonOther requirements: Python 2.7, TEpredict (provided with the PolyCTLDesigner), Biopython, NumPy, PyEvolve, and Python graphLicense: Creative Commons Attribution Non-Commercial License V2.0 (CC BY-NC 2.0)Any restrictions to use by non-academics: see CC BY-NC 2.0 licenseThe authors declare that they have no competing interests.SIB initiated the studies of polyepitope immunogens at the State Research Center of Virology and Biotechnology “Vector” and has developed the prototype of polyepitope rational design algorithm. DVA completed the concept, chose the models and algorithms, and implemented PolyCTLDesigner. DVA drafted the manuscript. SIB was involved in writing the manuscript and its critical revision and has given the final approval for the version to be published. Both authors read and approved the final manuscript.This file describes the short sample study of designing artificial poly-CTL-epitope antigen composed of 6 well studied HIV-1 CTL epitopes using PolyCTLDesigner.Click here for fileThis file contains the source code of PolyCTLDesigner together with a sample workflow script (designer.py).Click here for file


Low patency rates of saphenous vein grafts remain a major predicament in surgical revascularization. We examined a novel expandable external support device designed to mitigate causative factors for early and late graft failure.For this study, fourteen adult sheep underwent cardiac revascularization using two vein grafts for each; one to the LAD and the other to the obtuse marginal artery. One graft was supported with the device while the other served as a control. Target vessel was alternated between consecutive cases. The animals underwent immediate and late angiography and were then sacrificed for histopathologic evaluation.2 versus 23.1 mm^2 p < 0.02).Of the fourteen animals studied, three died peri-operatively (unrelated to device implanted), and ten survived the follow-up period. Among surviving animals, three grafts were thrombosed and one was occluded, all in the control group (p = 0.043). Quantitative angiographic evaluation revealed no difference between groups in immediate level of graft uniformity, with a coefficient-of-variance (CV%) of 7.39 in control versus 5.07 in the supported grafts, p = 0.082. At 12 weeks, there was a significant non-uniformity in the control grafts versus the supported grafts . In histopathologic evaluation, mean intimal area of the supported grafts was significantly lower than in the control grafts (11.2 mm^The expandable SVG external support system was found to be efficacious in reducing SVG’s non-uniform dilatation and neointimal formation in an animal model early after CABG. This novel technology may have the potential to improve SVG patency rates after surgical myocardial revascularization. Coronary artery disease (CAD) is the leading cause of death worldwide. The treWhile early vein graft occlusion is mainly due to technical aspects of the surgical procedure, intermediate and late graft failure results from an irregular remodeling and dilatation of the pressurized thin walled graft-9 with sThe concept of external support for vein grafts has been shown to be potentially effective in inhibiting intimal-hyperplasia and wall thickening in several animal studies-14. UnfoFourteen mature female Assaf sheep weighting 60-80 Kg form the basis of this study.Surgical procedures were conducted at the Technion, Israel Institute of Technology, Faculty of Medicine, Haifa, Israel after obtaining approval from the institute’s ethical committee for animal experiments. All procedures complied with the Animal Welfare Acts of 1966 (P.L. 89–544), as amended by the Animal Welfare Act of 1970 (P.L. 91–579) and 1976 (P.L. 94–279) and after obtaining approval from the institute’s ethical committee for animal experiments.Tel Aviv, Israel). The aim of the device is to provide vein grafts a shapeable, kink-resistant tight external support, to prevent possible kinking, non-uniform dilation, and wall thickening , factors known to cause early and late graft failure.The device we evaluated is made from braided cobalt-chromium-nickel-molybdenum-iron alloy fibers, forming an expandable external support apparatus  and Clopidogrel (150 mg/d) 72 hours prior to surgery and during the follow-up period. Activated Clotting Time (ACT) was measured prior to the performances of the first anastomoses and Heparin 5000 units were administrated to all animals. Additional doses were given to maintain ACT values above 300 seconds, until completion of the surgical procedure. Heparin was not reversed at the end of the procedure.Animals were placed in dorsal recumbence, and the saphenous vein was harvested through an uninterrupted leg incision, its side branch closed with small size hemoclips. A left lateral thoracotomy at the 3rd or 4th intercostal space was performed with a 20–25 cm long skin Incision with the LAD and larger obtuse-marginal arteries identified following pericardial incision. In each sheep, one vein graft was supported by the device and the other vein graft served as a control, alternating in every procedure, either to LAD or to the left circumflex territories, so that after measuring and trimming both grafts to the desired length, an appropriate device was threaded over only one of the grafts. A stabilizer  was used and grafts were then sutured to the coronary arteries using a continuous 7/0 polypropylene suture. After performing both anastomoses, the proximal coronary arteries were ligated and the device manually stretched open and shaped to cover the entire graft. The pericardium was then loosely reapproximated and the chest was closed with no reversal of heparin. General anesthesia was terminated and the sheep extubated upon resumption of vagal reflexes.Verification of graft patency and quantification of luminal diameter was achieved by immediate post-procedural angiography (t = 0) and at the end of the predetermined follow up (t = 12 weeks post-procedure). Following calibration relative to the 6 Fr diagnostic catheters, all graft angiographic images were divided to seven equal sections, in order to randomly measure the luminal diameters. Percentage coefficient of variance (%CV) was then calculated for each graft to compare diameter variance of the grafts at t = 0 and t = 12 weeks post procedure.Immediately following the second angiography t = 12 weeks) animals were sacrificed and grafts were harvested, photographed and examined for inflammation, injury or thrombosis . For each cross section, the lumen, neointima and medial layers were identified and measured with the Dotslide accompanying software. Five to seven cross sections in equal distances from proximal to the distal end were analyzed from each vein, representing 100% of the graft. Of note, plain determination of the average neointimal area along the entire graft from all cross-sections led to falsification of the true angiographic Figure in relation to its possible clinical implications. For example, a case of a distorted irregular graft with severe concentric wall thickening and stenosis proximally, along with significant remodeling and dilatation distally, would be paradoxically interpreted as a “healthy” regular graft. In order to interpret findings according to their true clinical relevance, only the three cross sections with the most extensive neointimal area were compared between supported and control graft.Cross- sections were then visualized with a BX51 microscope and thoroughly scanned using the Dotslide Due to the nature of the data collection and the desire to demonstrate the effect of external support on the morphology of vein grafts, it was decided to use a measure of variation. Since some correlation between mean values and standard deviations for each graft was evident, it was decided to use the percentage % coefficient of variation (%CV) as the parameter for the analysis. Small %CV values imply that all measurements across a vein are close to each other and thus good uniformity is obtained. Large %CV values indicate large differences in the diameter across the measured vein. This parameter was selected also because either increase (remodeling and dilatation) or decrease  in vein diameter is possible. Non-parametric matched-pairs (Wilcoxon Sign-Rank) test was used to compare the results from the externally supported and control vein grafts.A total of four animals out of the fourteen expired during the follow up period; three deaths occurred peri-operatively and one death occurred three weeks after the procedure. In all four we could not find any device-related event as depicted in Table At the end of the three months follow up, a second angiography demonstrated that all ten externally supported grafts were patent compared to nine of the control grafts. On this second angiographic evaluation, we found stenotic lesions, occlusion or irregularities in none of the externally supported grafts versus four of the non supported control grafts, p = 0.043. In late angiography we found no change in device position or in the extent of graft coverage by the device.Of note, one of the sheep had an aneurysmal dilatation of the control (non-supported) vein at the end of the follow up period, with normal appearance of the supported vein. Regrettably, although both veins appeared quite ordinary during surgery (with photographic documentation) only in this sheep did we fail to demonstrate the unsupported vein during early angiography and it was therefore excluded from angiographic analysis Figure d.Quantitative angiographic analysis of early and late angiographic studies was performed Figure  and coefIn gross pathology and histopathologic evaluation, all grafts and anastomotic sites appeared to be normal, with no apparent difference between grafts in terms of inflammatory cell infiltration and intimal laceration (injury). In the externally supported group the graft’s adventitia was incorporated into the device’s pores, fixated also by a thin layer of lucent connective tissue Figure  with no Intimal hyperplasia: The measured neointimal area on the histological slide was on average 100% greater in the control grafts compared to the supported grafts , with a mean intimal thickness of 0.65 mm in the support group vs. 0.89 mm in the control group, p = 0.11  and migration of smooth muscle cells into the vessel wall, is eventually the principal pathophysiological process leading to vein graft failure-18. ThisSince first hypothesized by Parsonnet et al. several Additionally, porous external wrapping was shown to promote significant peri-adventitial micro-vasculature, potentially reducing the oxidative stress of the vessel wall,21,23, aIn this report we describe the angiographic and histopathological effect of a novel supportive device that was designed to address key promoting factors for early and intermediate vein graft failure: kink, torsion, asymmetric dilatation-remodeling and the formation of thick ineffectual neointima. This device is tangentially elastic and un-kinkable but shapeable in its long axis to control pathway and position of the graft. The device is deployed in a slightly compressive manner, with no mounting appliances or adhesive materials.With no immediate angiographic differences, after three months the externally supported grafts maintained their angiographic appearance and luminal regularity , while the control grafts had an irregular appearance, with a significant change in the luminal coefficient of variance. Three non supported grafts had evident stenotic lesions (one graft was occluded). In histopathologic analysis, no difference between supported and control grafts was found in terms of vessel wall trauma or inflammation; yet, supported grafts had a significantly smaller (approximately 50%) intimal area. Furthermore there was evident thrombus formation within four of the controls versus none in of the supported group.This report has evident limitations with its sample size and follow up period, but these are no different than the other preclinical studies performed to evaluate the role of external support on vein grafts. Several years of follow up may be needed to fully demonstrate the exact impact of external support on vein graft occlusive disease. However, with the well defined information on the pathological phases that cause vein graft failure, adequate assumptions may well be made on final stages (atheromatous plaque), based on attenuation of earlier  occurrences, such as the differences we found after three months of follow up. In addition, the majority of the surviving animals that entered the angiographic and histopathologic evaluation had the device applied to the grafts anastomosed to the LAD (six out of ten sheep), hence a potential difference may have theoretically contributed to the different outcome between supported and non supported grafts due to possible dissimilarity in flow characteristics between different coronary territories. Importantly, some covariates , such as coronary target diameter, angiographic appearance and vascular bed, were not included in the analysis. These technical parameters might affect progression of occlusive disease in the both externally supported and control grafts. Finally, this study’s animal (sheep) model or the abrupt occlusion (ligation) that was inflicted on native coronary targets may not accurately reflect a human heart with chronic atherosclerotic disease. Still, among recent studies on venous external support, to our knowledge only in the current study was an actual CABG model actually used.Despite the unprecedented success of CABG procedures in the treatment of CAD, the main mitigating factor against excellent long-term results remains poor vein-graft patency rates. Vein-graft failure is a major cause for repeated surgical procedures, PCI’s, hospitalizations and other adverse events. However even with the growing awareness and dedication of the surgical community to using multiple arterial grafts, saphenous veins are, and will continue to be in the foreseeable future, the predominant grafts employed during surgical revascularization.Our current findings suggest that the expandable external support device that was examined in a realistic sheep model of surgical myocardial revascularization proved efficacious in reducing vein graft irregularity and intimal hyperplasia and may have the potential to improve patency and longevity of vein grafts deployed during clinical coronary revascularization. In a further clinical investigation, the first trial with this expandable support system is currently being conducted in the UK, to determine the potential of this device in future surgical practice.CABG: Coronary artery bypass grafting; LAD: Left anterior descending; LCX: Left circumflex; OM: Obtuse marginal; CV: Coefficient-of-variance; SVG: Saphenous vein graft; MACE: Major adverse cardiac events; ACT: Activated clotting time; CAD: Coronary artery disease; PCI: Percutanous coronary intervention.Yanai Ben-Gal MD - Medical director and ownership interest in VGS.David P. Taggart PHD, FRCS - Scientific advisory board of VGS, has ownership interest in VGS.Mathew R. Williams MD - Scientific advisory board of VGS, has ownership interest in VGS.Eyal Orion MD – CEO of VGS, investor and has ownership interest in VGS.Shmuel Banai MD - Scientific advisory board of VGS, has ownership interest in VGS.Rona Shofti PHD- Has ownership interest in VGS.Gideon Uretzky MD -None.Lyad Yosef BSc - Has ownership interest and employee of VGS.Gil Bolotin MD, PHD - Scientific advisory board of VGS and has ownership interest in VGS.YBG conceived of the study, design, writing the manuscript and revising. DT, helped in Conception, design and writing. MW helped to draft the manuscript. EO conceived of the study, design, analysis of data, active participating in the study and helped to draft the manuscript. GU and helped to draft the manuscript, RS active participation in the study SB helped to draft the manuscript. LY active participation in the study, analysis of data. GB active participation in the study, helped in conception, design and writing. All authors read and approved the final manuscript.


Lillian Leong, the chairperson of the organising committee and the outgoing past president of the AOSR.The theme of the meeting was “Radiology: from nano to cosmos” and the quality of the invited presentations and proffered papers was as good as, or better than, any international meeting I have ever attended.biij.One of the highlights was the Satyapal Aggarwal Memorial lecture which was given by Prof. Hedvig Hricak. Her lecture on advances in computed tomography (CT) was inspirational. The abstracts of the presentations will be available through We should be very proud of our young radiologists who presented their research and demonstrated to the world that the Asia-Pacific region is well poised to take advantage of the rapidly changing medical paradigm.I was very honoured to be elected as the President of the AOSR until 2008 when the 12th Congress will be held in Seoul, Korea. Over the next two years I shall represent the society at as many international meetings as possible and endeavour to visit as many of our 23 national societies as possible.The world continues to change rapidly and we must advance to keep pace with it. Economically the Asia Pacific region is a powerhouse and we must ensure that our medical care and radiology in particular keeps pace with developments in our region. We have many more challenges to face than the other great international societies but I sincerely believe that we are more than equal to the task before us.biij is the first step of a long journey.One of the biggest challenges is the enormous geographical scope of our region and the vast differences in the provision of medical care across the Asia-Pacific. The aim of AOSR is to ensure that radiology expands to meet these needs and joining forces with


Indirect reduction of dia-/metaphyseal fractures with minimally invasive implant application bridges the fracture zone in order to protect the soft-tissue and blood supply. The goal of this fixation strategy is to allow stable motion at the fracture site to achieve indirect bone healing with callus formation. However, concerns have arisen that the high axial stiffness and eccentric position of locked plating constructs may suppress interfragmentary motion and callus formation, particularly under the plate. The reason for this is an asymmetric fracture movement. The biological need for sufficient callus formation and secondary bone healing is three-dimensional micro movement in the fracture zone. The DLS was designed to allow for increased fracture site motion. The purpose of the current study was to determine the biomechanical effect of the DLS_5.0.Twelve surrogate bone models were used for analyzing the characteristics of the DLS_5.0. The axial stiffness and the interfragmentary motion of locked plating constructs with DLS were compared to conventional constructs with Locking Head Screws (LS_5.0). A quasi-static axial load of 0 to 2.5 kN was applied. Relative motion was measured.The dynamic system showed a biphasic axial stiffness distribution and provided a significant reduction of the initial axial stiffness of 74.4%. Additionally, the interfragmentary motion at the near cortex increased significantly from 0.033 mm to 0.210 mm (at 200N).The DLS may ultimately be an improvement over the angular stable plate osteosynthesis. The advantages of the angular stability are not only preserved but even supplemented by a dynamic element which leads to homogenous fracture movement and to a potentially uniform callus distribution. In recent years, extramedullary internal fixation techniques of long bone fractures have evolved from very rigid constructs to more flexible internal fixation constructs Recent studies have confirmed that axial stiffness of modern locked plating constructs is in some cases too high Several techniques have been described to decrease the stiffness of a locked plating construct i) axial stiffness and ii) interfragmentary motion . In this force range (0–2.5 kN), no plastic deformity of the implants was observed. The three-dimensional motion of each osteosynthesis was measured using the optical motion analysis system PONTOS 5M . Using an interface, the force measured by the load cell (testing machine) could be transferred to the optical motion system and processed by the software of the optical motion system. The axial stiffness was calculated using the applied force and the corresponding deviation in the z-axis. Furthermore, motion near the plate (cis-cortex) and far away from the plate (trans-cortex) was calculated. The data was analyzed with Matlab .The DLS is a new generation of locking screws that allows the surgeon to control the rigidity of plating constructs. The DLS pin-sleeve design combines locking technology with dynamic motion — the threaded sleeve anchors the DLS in the bone, while the pin locks the DLS with its standardized threaded head into Synthes locking plates . The plaFor measuring the 3D fracture motion we used the optical analysis system PONTOS 5 M . The system consists of two CCD (Charge-coupled device) cameras. For the detection of the motion passive markers are required. The points are recorded and tracked by the PONTOS software . The PONAll results were analyzed with a commercial statistical software package .In comparison to the LS, the DLS showed a biphasic stiffness distribution with distinct initial - and secondary stiffnesses. As shown in Interfragmentary motion was significantly greater at the near cortex +8 with tin vitro study was performed to assess the differences of a dynamic system using the DLS screws in an osteosynthesis construct compared to standard locking screws. We hypothesized that a dynamic system would result in more balanced fracture motion between the near and far cortices, which could theoretically improve callus formation and equalize callus distribution at the fracture site. To test the hypothesis of the current biomechanical study, two main topics were investigated: the axial stiffness and the interfragmentary motion. We found that stiffness was significantly decreased and near cortex motion was significantly increased in dynamic constructs. The physiological consequence of these altered biomechanics  will be addressed in an ongoing in vivo animal study.Delayed healing of long bone fractures remains a clinically significant problem. The recent popularity of locking plates has potentially contributed to this problem, as these implants are placed eccentrically and are extremely stiff. The goal of developing a new system with a new screw design was to theoretically retain the advantages of the successful locking screw concept by achieving high stability and bicortical screw bone interface. Additionally, however, this new design is intended to alter the overall axial stiffness of the implant, maintain the bending stiffness of proven plate devices, and increase the near cortex micromovement by more symmetrical axial stress distribution. The aim of our biomechanical investigation was to determine if the new dynamic locking screw was able to meet the functional requirements as theorized. A biomechanical In comparison to the non-dynamic screws, the dynamic system provided a significant reduction of the initial axial stiffness up to a certain applied axial load on the construct. While applying a load below 400 N, the axial stiffness of LS and DLS diverge from each other. In the range from 400 N to 2.5 kN however, the axial stiffness of both systems converged again . In otheAfter reaching the maximal range of motion limited by pin and sleeve contact, a sharp stiffness increase occurred, which we denoted the “secondary stiffness”. The secondary “axial” stiffness of the DLS was in the same range as the LS. In other words, the characteristics of the DLS equal those of the LS when higher loads are applied.Concerning patient safety, it can be noted that the positive effects of the DLS on fracture motion can be observed when a partial weight bearing of around 25 kg is maintained by the patient. But when higher loads are applied to the osteosynthesis, the DLS reacts like a conventional locking head screw. Because typical postoperative protocols for plated lower extremity fractures involve six to eight weeks of “toe-touch” weight bearing, our data can be extrapolated to being applicable in a clinical setting.When a conventional LS is used, the fracture motion on the far cortex is much higher than on the near cortex, because the interfragmentary motion is caused essentially by the bending of the plate As is shown in The current biomechanical study was performed in a bone surrogate model. This model was chosen because it enabled reproducible data and allowed for the detection of relatively small differences between the dynamic and the standard system. However, this study also had some limitations. As all tests were carried out with artificial bones, it did not reproduce the human biology. Therefore, we did not simulate the effect of osteoporosis on the two systems, and did not analyze the properties of different fracture types. But this was not in focus of the present study, in which the goal was solely to determine the effect of the DLS in an osteosynthesis construct.Our testing parameters were chosen deliberately to allow comparisons to previous work in the literature. Several previous studies have examined the biomechanics of “dynamic” locked plating systems. The DLS may ultimately be an improvement over the angular stable plate osteosynthesis. The advantages of the angular stability are not only preserved but even supplemented by a dynamic element which leads to homogenous fracture movement and to a potentially uniform callus distribution. The surgeon has the opportunity to deliberately influence the rigidity of an osteosynthesis through the DLS.


The following scientsts assisted the journal by reviewing manuscripts during the period October 1, 2012 to September 30, 2013. We gratefully acknowledge their critical evaluation and assistance in selecting articles for publication.