This Editorial is to commemorate “World AIDS Day” by increasing the awareness of AIDS, its treatment and prevention strategies.Education is the single most crucial factor that can eradicate AIDS.On the World AIDS Day, let us commit ourselves to learning and educating the world the scourge of AIDS.http://www.worldaidsday.org/about-world-aids-day.php)What is World AIDS Day? Between 2011-2015, World AIDS Days will have the theme of “Getting to Zero: Zero new HIV infections. Zero discrimination. Zero AIDS related deaths”. The World AIDS Campaign focuses on “Zero AIDS related deaths” signifies a push towards greater access to treatment for all; a call for governments and pharmaceutical companies to act now. It is a call to honor promises like the Abuja declaration and for African governments to at least hit targets for domestic spending on health and HIV. (http://en.wikipedia.org/wiki/World_AIDS_DayFurther Reading: AIDS Research and Therapy is publishing five high profile review articles to show our commitment in educating the world of the leading therapeutics and prevention efforts conducted by the dedicated research community. The articles span from Molecular Biology (Wilusz) to Humanities (Ramjee and Daniels) strategies. The goal has been to increase the awareness of therapeutics and suffering of the AIDS afflicted communities in post-HAART  era. Specifically:As a tribute on the World AIDS Day Dr. Wilusz presents persuasive arguments for novel potential therapeutics strategies that take into account the unique post-transcriptional events in HIV replication. For example, involvement of HIV TAT protein on highly structured 5’ end of HIV mRNAs and active repression of a promoter proximal signal for HIV polyadenylation.Hsu et al. review serious non-AIDS events (SNAEs) such as malignancies, cardiovascular, renal and hepatic, neurological and bone disorders causing morbidity and mortality in HIV-infected individuals. Since SNAEs are multifactorial, the authors have suggested several novel strategies and interventions to reduce the burden of these disorders.Similarly, the burden of metabolic complications (MC) in HAART treated individuals is high . The authors focus on the underlying mechanisms of MC highlighting pathophysiological and epidemiological aspects during HIV infection and during HAART treatment. Management of MC in HIV population is imperative.The article by Achhra and Boyds reviews the clinical trials related to sparing antiretroviral treatment of the major class of nucleoside reverse transcriptase inhibitor (NRTI). The authors described the regimens currently used in NRTI-sparing regimen, their advantages and disadvantages, and the majority of clinical trials related to them.Finally, but most importantly, sub-Saharan Africa bears the brunt of HIV infections accounting for almost two-thirds of world’s HIV infections (Ramjee and Daniels). The worst affected are younger women who have a larger prevalence of infection. Prevention strategies are crucial that take into consideration the socioeconomic and cultural aspects of women at large.It is expected that these articles, on World AIDS Day, will increase the awareness of the AIDS burden and the strategies to combat and prevent it. Let the entire world learn the implications of AIDS so that it can be eliminated in a humanitarian way.Kailash Gupta, Ph.D.Editor-in-ChiefAIDS Research and TherapyThe author declares that he has no competing interests.


The main scope of the HAIs control programs is quality of hospitalization improvement but the results of surveillance should also be used in benchmarking. The aim of this work was to assess and compare antibiotic usage in surgical site infections (SSI) treatment in Polish hospitals.Data used in this analysis were gathered in 13 hospitals participating in the program of active surveillance ofÂ HAIs in Poland between 2002/2006. In this time 96426 surgical procedures were done in hospitals which participated in the program. Altogether 2206 SSIs were detected in this population. Defined daily dose (DDD) was used for assessing antibiotic usage – per one SSI and per one operation.Antibiotic usage in analyzed population varied in wide range: from 6,9 DDD/SSI to 45,5 DDD/SSI or from 0,1DDD to 1,6DDD per one operation. Similar differences were observed also when data according to type of procedure were analyzed; in abdominal surgery antibiotic usage varied from 5,1DDD to 122,6DDD per one SSI or from 0,1DDD to 4,4DDD per one operation of this type. In cardiac surgery the rate varied from 5,3DDD to 19,0DDD per one SSI or from 0,8DDD to 2,6DDD per one operation. In orthopedic surgery those rates reached the following values: from 1,7DDD to 136,4DDD per one SSI or from 0,1 to 21,4 DDD per one procedure. There were no significant differences observed in microbial etiological factors and their resistance.Presented data indicate huge discrepancies of antibiotic usage for SSI treatment in analyzed Polish hospitals. The results confirm the need of continuous developing and training in the infection control area, but also the need of developing reliable tools for benchmarking different aspect of infection control results.None declared.


Swaziland is experiencing the world’s worst HIV and AIDS epidemic. Prevalence rose from four percent of antenatal clinic attendees in 1992 to 42.6 percent in 2004. The Report ‘Reviewing ‘Emergencies’ for Swaziland: Shifting the Paradigm in a New Era’ published in 2007 bought together social and economic indicators. It built a picture of the epidemic as a humanitarian emergency, requiring urgent action from international organisations, donors, and governments. Following a targeted communications effort, the report was believed to have raised the profile of the issue and Swaziland - a success story for HIV and AIDS research.Keen to understand how, where and why the report had an impact, Health Economics and HIV/AIDS Research Division commissioned an assessment to track and evaluate the influence of the research. This tapped into literature on the significance of understanding the research-to-policy interface. This paper outlines the report and its impact. It explores key findings from the assessment and suggests lessons for future research projects.The paper demonstrates that, although complex, and not without methodological issues, impact assessment of research can be of real value to researchers in understanding the research-to-policy interface.Only by gaining insight into this process can researchers move forward in delivering effective research. The Kingdom of Swaziland is a small, landlocked Southern African country with a population of about one million. In the 1980’s it experienced a significant upturn in investment and growth, benefiting from a regional advantage due to war in Mozambique and apartheid in South Africa. This was combined with relative political stability, sound macroeconomic policies, and a cheap and productive workforce, and resulted in significant inflows of foreign direct investment. Between 1985 and 1999 the growth rate was 6% and the well-being of the Swazi’s was on a modest upward trajectory 14]The application of Swaziland’s HIV prevalence rate to western countries, in Table 2 (page 8) of the report ‘stuck’ with some. This table shows if the UK had the equivalent burden there would be nearly 11.5 million British citizens infected. When presenting these data, it would be tailored to the audience – for example talking in Sweden the presenter said ‘Swaziland’s prevalence would be equivalent to 1.75 million Swedes being infected’.It is unsurprising that such dramatic predictions of the effects of the epidemic on the structure of the population would strike the reader. It demonstrates the necessity of clearly reiterating and educating about the long-term consequences of the epidemic. Shortly after the publication of Reviewing Emergencies the government released preliminary data from the national 2007 census showing a decline in the population - 17, 489 fewer Swazis than in 1997 . The serSuccessful dissemination was crucial, but wide dissemination is not the same as wide impact, and it cannot be assumed that the former naturally or inevitably leads to the latter . The comThe report was presented and formally discussed at a consultation in July 2007. It was available in print from October 2007, and a core set of power point slides was developed and presented to a range of organisations inside and beyond Swaziland. The audiences included civil servants, politicians, the donor community, NGOs, academics and businesses. Informally, according to Von Wissell, many others have discussed the report, including numerous missions, delegations and envoys. The report was made accessible online by HEARD  and NERCHEARD and NERCHA co-ordinated their efforts in communicating the findings. The delivery of the message itself was particularly significant. It had a coherence achieved by using the same slide set – presenters were ‘singing from the same song sheet.’ However, presentations were tailored to the audiences; Von Wissell presented to Swazi audiences in SiSwati; in Scandinavia the importance of donors was stressed.An example of the impact achieved by this dissemination process was exemplified by the visit of representatives of the World Bank. In November 2007, the Human Development Vice President and Country Director from the World Bank visited Swaziland to assess first-hand the country’s situation in human development and HIV and AIDS. They met with key government officials including the Minister of Finance, and Von Wissell. It was here that Von Wissell presented Reviewing Emergencies. One World Bank official described the effect of this by saying, “It was NERCHA’s presentation that brought home the gravity of the HIV/AIDS situation in Swaziland”, and subsequently the World Bank sent a mission to Swaziland to explore next steps for the Bank. The presentation of the report’s findings was critical to this decision.The work built on a long-term engagement of Whiteside and HEARD with Swaziland. This historical background is particularly important to both locate the research and the response to it. The timeline below shows the progression of HIV/AIDS in Swaziland through significant events and statistics, simultaneous to key examples of research conducted on the epidemic by HEARD and associates. As the timeline shows, Reviewing Emergencies built on three major reports in 1994, 2003 and 2006, which illustrated there was something going seriously wrong. Its message was credible - based on a history of research and evidence. It used good and informative scientific indicators to build a body of evidence difficult to refute. Furthermore, it was it was written at a critical time in Swaziland: with unusual levels of death; increasing numbers of orphans; and tuberculosis emerging as a major killer, the grim predictions of previous publications were no longer speculative, but reality .  . As one Significantly, the report was disseminated into a receptive network of researchers, policymakers and associates with whom HEARD and NERCHA had established links. As one respondent commented, “The wide network of individuals, organisations and donors with whom HEARD and NERCHA are affiliated were key to its wide reception”. The effectiveness of historic relationships such as these, built on both individual and institutional credibility cannot be underestimated. For example Whiteside had served on a UN Commission with the Deputy President of the World Bank, and is a Governor of a school in Swaziland; Von Wissell held the position of Minister of Trade and Industry and Minister of Health in previous governments. The message was delivered by people driven to see change and who could speak with authority. Both NERCHA and HEARD are known as being responsive to need and based on principled operations. In addition, the involvement of NERCHA - a Swazi based and Swazi run body - created an ‘ownership’ of the research and a further credibility to its message.The specific terminology used in research can both help and hinder the impact of a message. In Reviewing Emergencies the term and concept of a ‘long-wave emergency’ was particularly significant. A media respondent explained the term ‘emergency’ acted as a “hook”, giving journalists an attention-grabbing story, substantiated by genuine and shocking statistics. Titles such as ‘‘Swaziland: Declare HIV/AIDS a “humanitarian emergency”’  and “WheConversely however, concerns over the term ‘emergency’ were discussed at length at the Low-Middle-Income Countries meeting hosted by HEARD in February 2008. One respondent explained, “There is some reluctance on the part of donors/NGOs/civil society/government to call HIV/AIDS an ‘emergency’ because there seems to be fear that terming it so will result in short-term funding for a long-term problem. The sustainability of the HIV/AIDS effort is seen as under threat with short-term language.” This meeting concluded there was a need to marry the urgency of the crisis with a long-wave understanding of the future impact of HIV/AIDS on the country, and that ‘emergencies’ may not be the best term to represent this . A key mOur assessment identified five key limitations: the role of government was not addressed; using Malawi and Zambia as comparator countries had mixed results; issues around timing; the status of AIDS (and Swaziland) on the international agenda; and finally the calls for radical change may not be achievable.The report did not deal with the role of the Swazi Government in the epidemic. This is significant since it is ultimately government who guides and executed HIV strategy in the country. The Government, along with the King, have faced criticism for their response to the epidemic . One resThe historic and legal relationship between HEARD, NERCHA and the Swazi Government restrained the report’s ability to criticise. Prescribing how Swaziland should respond to the crisis was never the intention of the paper. Whiteside argued that attempting to change the behaviour of the Swazi Government was beyond the scope of what a researcher from outside of the country should attempt: “That is for the people of Swaziland to do.” Working with the government in a ‘strategic alliance’, rather than against is more productive. Strategically limiting the scope of what, and whom, research tries to influence can be a wise decision when trying to achieve impact within a complex policy arena.The report made comparisons between Swaziland and Zambia and Malawi, in order to demonstrate the scale of the emergency facing Swaziland. Despite the comparison having the desired effect of emphasising the scale of the Swazi’s crisis - some respondents referenced these comparative graphs as a striking and influential tool - it also had unintended consequences. Zambia and Malawi are both countries that, like Swaziland, compete for the attention of donors and development aid. By focusing all attention on Swaziland, the report appeared to belittle the issues faced by both Malawians and Zambians.‘Time’ is no doubt a barrier to the impact of the report, since research is usually most influential when first published. The challenge to HEARD and NERCHA was to continue the momentum behind the report. One respondent warned that the report “may lack academic credibility if it is not followed up by further research that is able to collect primary data.” The report aimed for both an immediate awareness of Swaziland’s epidemic, and a longer-term discussion on emergencies and low-middle income classifications. It is the latter of these in particular that needs to be worked at or risk a ‘fizzling out’ as time marches on.A number of significant international barriers threatened the impact of the report and indeed the issue of HIV/AIDS throughout Sub-Saharan Africa. Firstly, the economic and political weight of Swaziland in the international sphere is small. One frustrated interviewee described that “Swaziland is just not on the list”, as it is considered as insignificant by larger countries. Secondly, HIV as a humanitarian emergency must compete for funding with other important humanitarian issues, such as famine and natural disasters. One respondent described a ‘shift’ in global priorities to issues such as climate change, terrorism and the rising price of food. Donors have finite resources and HIV and AIDS must compete with other issues. HIV and AIDS was the global health issue receiving the most attention and funding but this will change, already a gap exists between pledges and funding .Finally, the report called for a change within the framework that international organisations use to identify countries’ level of development - that of income classification. It further calls for a shift in the paradigm of thinking on emergencies. “Effectively what this report says is that it can’t be business as usual”. Changing entrenched ways of thinking is a major task .‘Reviewing ‘Emergencies’ for Swaziland’ argued that socio-economic indicators show that the Swazi population is experiencing a humanitarian crisis comparable to countries besieged by conflict or struggling in the wake of a severe natural disaster. In the short-term, the report aimed to focus attention on Swaziland and what AIDS was doing to the country. It contributed to raising the profile of the plight of the Swazi people amongst donors and policy makers, described by one interviewee as a “catalyst for re-engagement”. In the medium-term, the report aimed to influence debate on the classification of low-middle income countries. This has proved more difficult. In the long-term, the report has seen some success in opening the debate on HIV/AIDS as a ‘long-wave emergency’. Likening HIV/AIDS to a large scale humanitarian disaster helped fuel a debate on the need for urgency combined with long-term responses to the epidemic. Donors, academics and NGOs have all engaged with the debate, but further advocacy and research is necessary to continue this, and see a shift in the current paradigm of thinking on what constitutes an ‘emergency.’Developing a better understanding of the relationship between research and policy impact is vital to advancing the influence of SRH and HIV and AIDS research. Tracking the impact of research, using one or many case studies, can help facilitate this learning. Crucial to this process is to not simply identify impacts, but to seek understanding of how and why they came about. Of particular use for developing effective research in the future is identifying where intended impact has not been achieved and why. The assessment of the impact of Reviewing Emergencies attempted to do exactly this.Drawing from the assessment, the following lessons may help inform future SRH and HIV/AIDS research. Communication is critical. The original work - collecting existing data to tell one clear story - is a striking way to demonstrate the reach and scale of disease impact; the demographic implications of AIDS powerfully communicated the severity of the epidemic; a targeted, tailored and cohesive dissemination effort helped facilitate the impact of research; sustained advocacy which is vital in keeping momentum for a message, should be reflected in planning and resources; further publications validating and extending a message are a good way to do this; and terminology can help or hinder the impact of a message.Context and timing may be beyond the control of researchers but can significantly influence the uptake of research. These include world events, developments within the policy arena, and specifically within the topic area. If these conditions align in the favour of the research the impact may be much greater, therefore awareness of this, and careful timing of publications and advocacy efforts could maximise impact.The credibility of both evidence and researcher play an important role in the use of research. Historical integrity of the evidence and an established researcher (or institution) can foster confidence in the use of research and increase the likelihood of it being used to inform policy. Established relationships and networks between individuals and institutions can guarantee an audience and encourage a dialogue on the findings. ‘Ownership’ of research, by the people it affects, is a powerful way to ensure both credibility and drive behind the message.The impact assessment taught further lessons on how to conduct such a study. An assessment should ideally be planned in advance, facilitating the process of ‘tracking’ and information gathering; careful attention should be paid to the measurement and analysis process – if basing the study on qualitative data, how will this be analysed and how will the effects of bias be mitigated; the ‘net should be cast wide’ when considering areas of potential impact, recognising both the multiplicity of policy players and the potential for unintended impacts; understand that impacts may also change over time; and ultimately, to understand why an impact took place, the socio-cultural, political and economic context must be considered.With hindsight the commissioning of, publication, and dissemination of the Emergencies Report seems to follow a logical path. The sense of frustration and the need to provide evidence led to this innovative work. It is our belief that it achieved many of its goals and spurred an international dialogue around the issues. The evaluation taught us additional lessons, which can be applied to help maximise the impact of research in the future.This article critically reflects on a research project in which the authors have been involved.AW conceptualised the paper, and was co-author to the original study entitled ‘Reviewing ‘Emergencies’ for Swaziland’ (2007). AW also edited the manuscript. FH drafted the manuscript, with input from AW. FH was the author of the study ‘Assessing the Impact of ‘Reviewing ‘Emergencies’ for Swaziland: Shifting the Paradigm in a New Era’ (2008). Both authors read and approved the final manuscript.AW is Director of the health economics and HIV/AIDS Research Division (HEARD) at the University of KwaZulu-Natal. He has an MA from the School of Development Studies at the University of KwaZulu-Natal and a D Econ from the University of Natal.FH has an MSc Development Management at the Department of International Development from the London School of Economics and MA Economics and Politics from Edinburgh University. She was a visiting fellow to HEARD in 2008.


Resistance to antibiotics has increased recently to a dramatic extend, and the pipeline of new antibiotics is almost dry for the five next years. Failures happen already for trivial community acquired infections, like pyelonephritis, or peritonitis, and this is likely to increase. Difficult surgical procedures, transplants, and other immunosuppressive therapies will become far more risky. Resistance is mainly due to an excessive usage of antibiotics, in all sectors, including the animal one. Action is urgently needed. Therefore, an alliance against MDRO has been recently created, which includes health care professionals, consumers, health managers, and politicians. The document highlights the different proposed measures, and represents a strong consensus between the different professionals, including general practicionners, and veterinarians. After saving countless lives, antibiotics are in danger of losing their effectiveness. The reaAntibiotics are unique medications in that their targets (bacteria) are living organisms capable of adapting by developing mechanisms that confer resistance to antibiotics . Despite this feature shared by no other medication, antibiotic prescription is viewed as a trivial act, both in humans and in animals. Limited improvements have been achieved, but France remains among the heaviest consumers of antibiotics in Europe.Clearly, there is a pressing need to protect the effectiveness of antibiotics  via proactive strategies similar to those used to save endangered species, in keeping with the concept of sustainable development. Antibiotics are unique medications and must be prescribed only with good reason. Each prescription should be thought carefully, and the short-term benefits to the patient  should be weighed against two categories of deleterious effects: short-term adverse effects on the patient – such as manifestations of intolerance or allergies, which are unacceptable if the antibiotic is not indispensable – and negative medium-term effects on bacterial ecology, with selection of MDR organisms. Selected MDR organisms subsequently cause infections in the community, of which the patient is a member. The prescription of antibiotics must be the result of a complex deliberative process, whose components must obey evidence-based rules. This objective of achieving rational antibiotic prescribing practices requires an orchestrated effort by both the healthcare system users and the prescribers. Other strategies should be implemented concomitantly, such as campaigns to promote immunizations known to exert antibiotic-sparing effects .The World Alliance against Resistance to antibiotics (WAAR) is a crosscutting action plan designed by a small group of professionals and by the patient-support group LIEN to deal with the current emergency. This plan involves healthcare providers , veterinary medicine professionals, and the food industry. It is of immediate significance for current and future users of the healthcare system, as well as for all citizens.The Alliance is a group of about 350 individuals representing all the key stakeholders including healthcare system users . The scientific committee is composed of 80 international physicians of considerable renown. The Alliance receives support from 50 learned societies or professional groups in France and throughout the world. It is a nonprofit organization (French law of 1901) open to professionals and users worldwide.SAFEGUARDING ANTIBIOTICS requires an orchestrated effort carried out jointly by healthcare system users and prescribers (in the broad sense of the term). Therefore, WAAR has chosen as its primary objective to raise awareness among all stakeholders of the urgency and magnitude of the threat. WAAR must lobby actively for antibiotics beyond the circle of insiders in order to raise awareness among policy-makers, international health organizations , and the entire population. The Alliance, in France is designed to serve as a complement to two French nationwide programs, the Antibiotic Alertness Program for 2011–2016 and the Antibiotic Resistance Minimization in Veterinary Medicine Program. The Alliance has no conflicts of interest.WAAR advocates a number of immediate measures:a much more cautious and controlled approach to the use of antibiotics, in all areas;relentless efforts to prevent the cross-transmission of MDR organisms both in hospitals and in private practice;the expansion of basic and applied research efforts in human and veterinary medicine;the development of new antibiotics, including via the identification of methods based on antiadhesion molecules to combat specific bacterial species;the development of antibiotics or treatment strategies for veterinary medicine that have the smallest possible ecological impact;the development of new vaccines;a much more widespread use of diagnostic tests, with the goal of limiting the prescription of antibiotics to proven bacterial infections;a ban of broad spectrum antibiotic use without an attempt to diagnose the cause of the infectionincreased surveillance of antibiotic resistance and use, with regular feedback to healthcare professionals and the public;education and training programs for healthcare professionals and consumers;the rapid implementation of antibiotic programs for humans and animals, by making the necessary resources available.Direction Générale de la Santé, DGS) and of the Antibiotic Resistance Minimization in Veterinary Medicine Program. However, the Alliance advocates much stronger measures to be implemented on an emergency basis, most notably regarding the modalities of antibiotic prescription.Some of these measures are part of the Antibiotic Alertness Program for 2011–2016 implemented by the French National Health Agency  is currently conducting an information campaign. This measure needs to be intensified, and information efforts must be thought through and developed in partnership with the key stakeholders, in a manner that is consistent with other components of the strategy for safeguarding antibiotics. The information campaign targeting healthcare professionals and consumers should include advice on basic hygiene and on the prevention of cross-transmission. These two topics should be dealt with in a well-orchestrated manner.A vast information campaign on antibiotics targeting physicians, veterinarians, pharmacists and consumers is needed to raise awareness of the threat to the life-saving potential of antibiotics. Consumers must be reminded that antibiotics have no effect on viruses, which account for the overwhelming majority of respiratory tract infections. Both physicians and consumers should feel accountable whenever an antibiotic is prescribed. The French public health insurance system . Each center should have a telephone hotline for hospitals and another for private practices. Both hotlines should be operated by paid professionals. Thus, each region of the country should have a network of well-trained antibiotic stewards who can provide advice by telephone around the clock 7 days a week to healthcare facilities that have no antibiotic stewards on their staff.Awareness of these networks and antibiotic stewards should be increased via vast communication campaigns targeting professionals, and incentives to encourage the use of these networks should be provided.The entire process of antibiotic prescription and delivery to each patient identified by name should be entered into secure databanks.http://www.antibioclic.com).Decision-making aids complying with suppress french recommendations should be widely disseminated , and restrictions should be placed on the use in animals of antibiotics that are critical to humans  (Reference 26 of the veterinary medicine program).A study should be conducted to evaluate the prescription and delivery of antibiotics by veterinarians and the consequences on antibiotic consumption. European directives must be developed promptly to revise marketing practices related to the promotion and sales of antibiotics (reference 29 of the veterinary medicine program).A vast program of university training and continuing education for professionals should be set up. Curricula for human and animal healthcare professionals should give priority to the wise use of antibiotics and to good hygiene practices, most notably those designed to limit the cross-transmission of microorganisms. In these areas, measures designed to modify current practices should receive recognition (P4P?).http://www.e-bug.eu) designed to raise awareness of these objectives among schoolchildren should be widely advertised.The European program e-bug Each antibiotic prescription to hospital patients should require validation by a senior physician.An attempt to isolate a microbiological pathogen needs to be undertaken for all patients that receive broad spectrum antibioticsGeneric drugs should be used only if they have been proven as effective as the corresponding proprietary drugs.Preference should be given to antibiotics that have limited ecological effects, and the most recent antibiotics should be used rationally.Antibiotic treatment durations should be kept as short as possible, and when appropriate antibiotics should be stopped after a careful reappraisal .Antibiotics should be delivered only in the amount prescribed  to minimize self-medication; this measure has already been adopted in other countries.A specific prescription form should be developed for antibiotics at high risk for inducing ecological effects, such as third-generation cephalosporins, fluoroquinolones, and carbapenems.The measures taken for human medicine should be adapted to veterinary medicine, based on the specific features of animal care. Routine prophylactic antibiotic treatment of livestock and fish must be prohibited, except when the presence of risk factors has been documented. After the onset of an outbreak in a farm, early prophylactic antibiotic treatment of all animals or metaphylactic antibiotic treatment of selected subgroups may be in order. Only the amount of antibiotics corresponding to the prescription should be delivered. The treatment should be brief, in order to minimize its ecological impact. The price or price margin of veterinary antibiotics should be set according to the benefits they produce.Effective antibiotics are an endangered species, and their use should be subsumed to ecological principles and integrated within a global sustained development concept. Because they of considerable universal value, antibiotics deserve to be protected.The health threats due to fecal contamination with MDR bacteria require vigorous action. Under everyday conditions, person-to-person transmission of bacteria occurs chiefly via the hands. Hand hygiene practices must be improved in the community across the range of social activities. For example, individuals must learn to sneeze and cough into the crook of the elbow if immediate hand disinfection is not possible. The use of hydroalcoholic hand rubs should be encouraged in healthcare settings and, under some circumstances, in the community.Hospitalized patients known to carry MDR bacteria should be isolated. In addition, patients with risk factors such as multiple hospital admissions, medical evacuation from abroad, and hospital admission abroad within the past year should be screened and isolated until the results are available. The best course of action may vary across MDR organisms. More generally, strict adhesion to standard hygiene recommendations is crucial with all patients.In livestock farms, good hygiene and appropriate facilities and practices are indispensable. Hygiene is critically important wherever animals are raised.Waste products from hospitals and livestock farms should be processed appropriately. There is a need for rethinking waste treatment plant operations in order to prevent contamination of soil and water, as antibiotics continue to select MDR organisms in the natural environment.Resources should be made available to improve the detection of resistant bacteria in drinking water and in foods such as meat and fish.Intensified research efforts are needed to elucidate the epidemiological mechanisms underlying bacterial resistance and to develop new antibiotics, new vaccines, and non-antibiotic anti-infectious agents for use in human and veterinary medicine. Research into the behaviors that explain the greater consumption of antibiotics in France compared to other European countries may help to design effective campaigns targeting prescribers and the public, with the goal of improving antibiotic usage.Financial incentives should be created to support startup companies focusing on the development of new products, as well as pharmaceutical companies exhibiting a firm commitment to a policy of good antibiotic usage.Existing rapid diagnostic tests (RDTs) should be used widely and appropriately. They include the rapid strep test for streptococcal pharyngitis and urinary dipstick tests. In infections of greater severity, such as pneumonia, the C-reactive protein or procalcitonin level can be measured in a sample of capillary blood collected at the bedside . In many cases, these rapid and simple tests can rule out a bacterial infection, thereby avoiding the use of antibiotics. They should be reimbursed by statutory health insurance systems. Support should be provided to the development of tests characterized by greater specificity and sensitivity, as well as of multifunction tests.All these crucial measures are being advocated by professionals, and professionals should be in charge of control processes and training. If these measures are not taken now, then the near future may witness the implementation on an emergency basis of compulsory measures that may be either inappropriate or difficult to accept.Europe has an outstanding system for monitoring antibiotic resistance patterns and antibiotic use. However, further surveillance efforts are needed in the community and in veterinary medicine. Furthermore, surveillance data should be communicated in simple terms and at regular intervals to healthcare professionals, decision-makers, and the public, both for the entire country and for each region.The objective of the French nationwide program for humans and animals is an at least 25% decrease in antibiotic consumption over 5 years.WAAR advocates a 30% decrease over 3 years, in both humans and animals, to rapidly reach the mean value for European countries.In conjunction with hygiene practices in hospitals and in the community , this measure would be expected to stabilize resistance levels at their current values or perhaps even to obtain a decrease.Staphylococcus aureus , Escherichia coli resistant to third-generation cephalosporins , glycopeptide-resistant enterococci (VRE) , and carbapenem-resistant Enterobacteriaceae (CRE)  this could vary according to countries.WAAR advocates the following resistance indicators and target values: penicillin-resistant pneumococci , methicillin-resistant The profile and amount of antibiotics prescribed by each physician working in office practice is monitored in France by the statutory health insurance system. The data thus obtained should provide a tool for physician self-evaluation and quality-indicator development. However, the monitoring procedure needs to be sharpened, in particular by factoring in the profile of each physician’s patient caseload. One approach may be to have professional organizations conduct critical reviews of random samples of patient files.To safeguard the small number of antibiotics that are still effective, and to protect the few antibiotics that will be introduced in the future, awareness must be raised throughout the country, on an emergency basis. Prescribers and consumers should work together to achieve this objective.JOIN US NOW, by contactingJean Carlet, president of WAAR, 9 rue de la terrasse 94000 Créteil, FRANCEjeancarlet@gmail.cofm.Your help is vital!!Members of the Alliance: Laurent Aaron, Jacques Acar, Mansour Adéoti (Secretary of the RIPAQS), Corinne Alberti, Serge Alfandari, Antoine Andremont, François Angouluant, Djillali Annane (Dean of the Paris Ouest University), Gilles Antoniotti, Jean-Pierre Aquino, Anne-Marie Armentera De Saxcé (Director of the Rothschild Foundation), Anne Arnera-Carlet, Pascale Arnould (President of the French Society for Primary Care), Pascal Astagneau (Director of the Paris North CCLIN), Claude Attali, Fréderic Auber, Jean-Pierre Aubert, Elisabeth Autret-Leca, Elie Azoulay, Françoise Ballereau, Gérard Bapt (representative of the Haute Garonne district), Géraldine Bardon, Jean Pierre Bedos, Sibylle Belivacqua, Fethi Bensalem, Nelly Beon André, Patrick Berche (Dean of the Paris 5 University), Frederique Bergheau, Gilles Berrut, Philippe Berthelot , FrederiqueBeuhourry-Sassus, Edouard Bingen, Jacques Birgé, Sandra Biscardi, Marie-Claude Bongrand, François Bourdillon, Alain Bousquet-Melou, Jean Brami, Stephane Bretagne, Christian Brun-Buisson, Fabrice Bruneel, Yves Bur (representative of the Bas Rhin district), Sandrine Buscail, Christelle Cabon, Emmanuelle Cambau, Philippe Caranco, Camille Carlet, Florian Carlet, Jean Carlet, François Caron (president of the ACAI), Alain-Michel Ceretti, Pascale Chaize, Martin Chalume Allier district), Pierre Charbonneau, Christian Chavanet, Jean Chastre, Jean-Daniel Chiche (president-elect of the European Society of Intensive Care Medicine), Christian Chidiac, Fabrice Chopin, Olivier Chosidow, Patrick Choutet, André Cicollela , Robert Cohen, Bruno Coignard, Catherine Cordonnier, René Courcol, Aline Creuwels, Vincent Dacquet, Laurent Degos , Valérie Delbos, Jean-François Delfraissy (Director of the ANRS and of the ITMO for infectious diseases), Pierre Dellamonica, Frederic Delille, Marie-Claude Demachy, Corinne Denis, Marie-Helène Denninger, Jean Claude Desenclos, Nicole Desplaces, Jean-François Dhainaut (Director of the High Commission on Biotechnologies), Isabelle Dijols-Lecuyer, Than Doco-Lecompte, Jean Doucet, Pierre-Louis Druais (president of the College of Primary-Care Physicians), Catherine Dumartin, Marie-Françoise Dumay, Michel Dupon , Jacques Fabry, Bruno Fantin, Albert Faye, Nathalie Floret, Sandra Fournier, Irène Frachon, Bertrand Gachot, Jacques Gaillat, Tatiana Galperine, Karine Gambarotto, Lisa Garcia, Bernard Garo, Anne Gaschet, Remy Gauzit, Gaetan Gavazzi, Louise Gazagne, Chistian Ghasarossian, Jacques Gilquin, Olivier Goeau-Brissonniere , Fred Goldstein, Alix Greder, Amandine Grain, Benoit Guery, Catherine Guignabert, Loic Guillevin , Laurent Gutmann, Joseph Hajjar, Rodolphe Halama, Olivier Hanon, Yves Hansmann, Isabelle Hau, Veronique Hentgen, Jean-Pierre Hermet (user), Celine Hernandez, Laurent Hocqueloux, Bruno Housset, Sophie Hubiche, Benoit Huc, Françoise Ichou (writer), Vincent Jarlier, Dominique Jean, Laurent Jouffroy , Karine Kadri, Axel Kahn , François Kidd, Pierre Kilidjean (user), Serge Kouzan, Jean-Philippe Lacour (president of the French Society for Dermatology), Matthieu Lafaurie, Thierry Lavigne, Olivier Lehiani, Jean-Patrick Lajonchere , Jérome Larché, Gérard Laroussinie, Peggy Larroude, Anne-Marie Lavenaire, Thierry Lavigne, Christine Lawrence, Agnès Lefort, Guy Lefrand (representative of the Eure 1ec district), Hervé Le Louet, Alain Lepape, Joel Leroy, Xavier Lescure, Pierre Lombrail , Matthie Lorrot, Olivier Lortholary, Anne Lotthe, Jean Christophe Lucet, Jean-Yves Madec, Alexandra Mailles, Jacky Maillet, Jean Luc Mainardi, Alain Manuguerra, Carole Marchand, Bruno Marchou, Emmanuelle Martin, Claude-Denis Martin, Alain Martinot, Patrice Massip, Sophie Matheron, Nathalie Maubourget, Thierry May, Olivier Meunier, Noel Milpied (president of the French Society for Bone Marrow Transplantation), Christelle Miquel, Benoit Misset, Jean Michel Molina, Philippe Montravers, Gérard Moulin, Pascale Moulin, Gilbert Mouthon, Cécile Mourlan, Marie-Hélène Nicolas-Chanoine (president of the Onerba), Gérard Nitenberg, Patrice Nordmann, Jocelyne Ouanich, Bernard Page, Pierre Parneix (director of the South-West CCLIN), Olivier Patey, Yves Pean, Martine Peres, Pascal Perez, Christian Perronne (president of the French Federation of Infectiologists), Dominique Peyramond, François Philippart, Marie-Laure Pibarot, Marie-Cecile Ploy, Anny Poursinoff (EELV representative of the Yvelines district), Philippe Pucheu , Celine Pulcini, Christian Rabaud (president of the French Society for Infectious Diseases), Claude Rambaud (president of the LIEN), Bernard Régnier, Jean Reignier (president of the Society for French-Speaking Intensivists), Vincent Renard , Jean-Claude Reveil, Patricia Ribaud, Agnès Riche, Jérome Robert, France Roblot, Olivier Romain, Monique Rothan-Tondeur, Willy Rozenbaum, Genevieve Ruault, Laurence Safont, Julien Saison, Marie Christine Saux , Anne Savey (director of the South-East CCLIN), Catherine Schlemmer, Benoit Schlemmer (Dean of the Paris 7 University), Jean-Luc Schmidt, Martine Sinègre, Muriel Soulier-Majidi, Jean-Philippe Tabut, Fabienne Tamion, Pierre Tattevin, Soraya Terzaki, Laurent Thiriet, Jean-François Timsit, François Trémolières, Dominique Trivier, Michel Troadec, Jean-Paul Stahl, Garance Upham , Bruno Valeyre (president of the Society for French-Speaking Pulmonologists), Dominique Valla, Emmanuelle Varon, Homero Vasquez, Nathalie Vauvarin, Agnes Vincent, Daniel Vittecoq (president of the AMM), Pascal Voiriot, Pierre Weinbreck , Michel Wolff, Yazdan Yasdanpanah, Jean-Ralph Zahar, Daniel Zara Goni, and Jean-Marc ZizaInternational Scientific Committee: Fekri Abroug , Murat Akova , Fatma Amer (Egypt), Massimo Antonelli , Apostolos Armaganidis , Antonio Artigas , Fernando Baquero (Spain), Yaron Bar-Lavie , Thierry Calandra , Abdelfattha Chabib , Annie Chalfine , Nathan Clumeck , Jonathan Cohen (UK), Peter Collignon , François Clergue , George Dimopoulos , Georges Ducel , Ricardo Durlach (Argentina), Naima Elmdaghri , Dan Engelhard , Annegret Franf-Karwautz (Austria), Petra Gastmeier , Abdul Ghafar (India), Donald Goldmann , Herman Goossens , Thomas Gottlieb , Manuel Guzman (Venezuela), Inge Gyssens , Fadi Haddad , Stephan Harbarth , Hakima Himmich , Salih Hoçoglu , Waleria Hryniewicz , Namita Jaggi , Mitsuo Kaku , Igor Karpov (Belarus), François Kidd , Badreddine Kilani , Georges Khalil , Oui-Chang Kim , Gabriel Levy Hara (Argentina), Elisabeth Heisbourg (Luxemburg), Pierre-François Laterre , Moi-Lin Ling (Singapore), John McGowan , Dimitri Matamis , Kamal Marhoum El Filali , Shaheen Mehta , Maria-Lisa Moro , Dilip Natwani , Babacar N’Doye , Steve Opal , Trish Perl , José-Arthur Paiva , Mercedes Palomar , Didier Pittet , Jean-Francois Pittet , Peter Pronovost , Jérome Pugin , Rosana Richtman (Brazil), Vladimir Rudnov (Russia), Wing-Hong Seto , Evelina Tacconelli , Falilatou Tchaline (Togo), Jordi Valles , Christian van Delden , Ethan Rubinstein , Christina Vandenbroucke (The Netherlands), Jos van Der Meer , Homero Vasquez (Chile), Jean-Louis Vincent , Eric Vohr , Andreas Voss , Jeanine Wiener-Kronish , Emile Zein , Josephine Zoungrana (Burkina Faso).-Société Française de Médecine Générale (SFMG), Société de Pathologie Infectieuse de Langue Française (SPILF), Société Française de Microbiologie (SFM), Société Française d’Hygiène Hospitalière (SF2H), Société Française de Santé Publique (SFSP), Société de Réanimation de Langue Française (SRLF), Société Française d’Anesthésie Réanimation (SFAR), Société de Pneumologie de Langue Française (SPLF), Société Libanaise de Médecine Interne (SLMI), Société Française de Greffe de Moelle (SFGM), Société Française de Gériatrie et Gérontologie (SFGG), Association Tunisienne de Réanimation (ATR), Société Tunisienne de Pathologie Infectieuse (STPI), Sociedale Paulista de Infectiologia-Brésil, Société Belge de Microbiologie Clinique (BVIKM/SBIMC), Société Marocaine de Maladies Infectieuses (SMMI), Société Française de Dermatologie (SFD), Australasian Society for Infectious Diseases (ASID), Australian Society for Antimicrobials (ASA), Austrian Antibiotic Stewardship Group, Hellenic Society of Intensive Care, Société Française de Médicine Interne (SFMI), and European Society of Intensive Care Medicine (ESICM).Association Le LIEN, Association Le CISS, Fédération des Spécialités Médicales (FSM), Association pour la chimiothérapie anti-infectieuse (ACAI),Observatoire National d’épidémiologie de la Resistance Bactérienne aux antibiotiques (ONERBA),Collège National des Généralistes Enseignants (CNGE), Collège national de médecine générale (CNMG), Fédération Française de pneumologie (FFP), Groupe de Pathologie Infectieuse en Pédiatrie (GPIP), Collège des Enseignants de Maladies Infectieuses (CEMIT), Fédération Française d’Infectiologie (FFI), Collège National de Pathologie Infectieuse (CNPI), Institut Maurice Rapin (IMR), Medqual , Antibiolor (C Rabaud), Observatoire du Risque Infectieux en Gériatrie , Le Forum des bio-hygiénistes, Arab Alliance for a prudent use of antimicrobials (Ar-Apua), Association Phagespoir, Programme National de lutte contre l’infection nosocomiale , Réseau International pour la Planification et l’Amélioration de la Qualité, et de la Sécurité dans Services de Santé en Afrique (RIPAQS), Infection Prevention and Control African Network (IPCAN), Association des médecins coordonnateurs en EHPAD, Association de Lutte contre les Infections Associées aux Soins (ALIAS), Ligue Africaine des Associations pour la Sécurité des patients (LIASEP), Portuguese alliance for the preservation of the antibiotic, ESGAP working group (ESCMID), and Association des victimes d’infection nosocomiale (ADVIN).


We started diagnosing Bundle Branch Block about 100 years ago on dog models .Today, we have conventional criteria for diagnosing LBBB, including QRS duration>120 msec, QS or rS in lead V1, Monophasic R wave with no Q wave in lead V6 and I3, ACC/AHA/HRS added notched R wave in lead I,aVL, V5, and V6, and occasional RS pattern in V5 and V6 (In case rate dependent LBBB develops, you can see the disappearance of the q wave in V6, then initial slurring of R wave and delayed increased intrinsicoid deflection. More complete LBBB causes notched plateau after initial peaked R wave .LBB has anterior fascicle, posterior fascicle, and sometimes a septal fascicle .Blocking the left bundle may cause septal force to disappear; therefore, no initial R wave can be detected in V1 or Q wave in I, V5, and V6, but that is not always the case (Sometimes, septal MI causes initial Q in the lateral leads and initial R wave in V1. Also, Grants and Doge found initial septal force in 40% of their cases with LBBB .Accordingly, initial septal force should not be considered as a diagnostic criterion for LBBB. Widening of QRS may occur in LBBB as well as many other conditions, such as LVH, RVH, and IVCD. Sometimes, LBBB also causes minimally increased width in QRS named incomplete LBBB.Wilson compared dogs and humans and suggested 120 msec. as the cut-off point for diagnosing LBB .They showed that when LBB is blocked, 40 msec. are required for septal depolarization, then 50 msec to reach the posterolateral wall, and finally 50 msec to complete posterolateral wall activations. Moreover, they suggested 140 msec. for males and 130 msec. for females for diagnosis of LBBB. The most consistent finding in LBBB patients seems to be mid QRS notching or slurring which is best seen in I, aVl, V5, and V6 (This mid QRS notching shows two vectors that are in the relatively same direction but one is minimally delayed. The first vector shows depolarization of endocardium of the left ventricle, while the second one seem to show depolarization of epicardium of the posterolateral wall .Diagnosis of LBBB using ECG may be accompanied by some errors as high as 30 % of cases. Therefore, LBBB is better to be confirmed through intracardiac mapping techniques. However, only a limited number of studies have investigated the issue. Josephson nicely mapped about 40 patients and his consistent finding was nearly 40-msec delay between RV endocardium and LV endocardium in LBBB patients .Furthermore, Vassallo et al. showed that only ⅔ of the LBBB patient diagnosed on ECG had more than 40 msec. trans-septal activation on intracardiac mapping; thus, the accuracy of the routine criteria for diagnosis of LBBB was only 70% .In 2004, Auricchio performed 3-dimensional contact and noncontact mapping for LBBB patient and his results showed the same accuracy as the conventional ECG criteria .All these lead us to wrong diagnosis of LBBB in ⅓ of our patients and this is the exact number of non-responders in CRT patients where diagnosis of LBBB is a pre- requisites .Considering what was mentioned above, new criteria for LBBB are needed and the best suggestions include:QRS more than 140 msec for males and 130 msec for femalesNotching of peak QRS in at least two leads from I,avL, V1, V2, V5, and V6QS or rS in lead V1 .This new definition can be used for picking up the cases of CRT implantation and the patients follow up may solve the mystery of non-responders in CRT patients.


BLM gene cause Bloom syndrome, notable for early development of tumors in a broad variety of tissues. On the basis of sequence similarity, BLM has been identified as one of the five human homologs of RecQ from Escherichia coli. Nevertheless, biochemical characterization of the BLM protein indicates far greater functional similarity to the E. coli RecG protein and there is no known RecG homolog in human cells. To explore the possibility that the shared biochemistries of BLM and RecG may represent an example of convergent evolution of cellular function where in humans BLM has evolved to fulfill the genomic stabilization role of RecG, we determined whether expression of RecG in human BLM-deficient cells could suppress established functional cellular Bloom syndrome phenotypes. We found that RecG can indeed largely suppress both the definitive elevated sister chromatid exchange phenotype and the more recently demonstrated gene cluster instability phenotype of BLM-deficient cells. In contrast, expression of RecG has no impact on either of these phenotypes in human cells with functional BLM protein. These results suggest that the combination of biochemical activities shared by RecG and BLM fill the same evolutionary niche in preserving genomic integrity without requiring exactly identical molecular mechanisms.Defects in the human  E. coli RecQ protein: BLM, WRN, RECQL, RECQL4 and RECQL5. These proteins are all implicated in preserving genomic integrity . Funcpulation.in vitro activities of BLM demonstrates significant similarities to the biochemistry of the E. coli RecG DNA translocase protein. Both BLM[′-OH ssDNA has invaded a homologous DNA duplex, although the mechanism by which RecG carries out this reaction is less well established[Sequence homology of BLM with RecQ notwithstanding, characterization of the Both BLM,5 and ReBoth BLM,7 can biBoth BLM,9 and ReBoth BLM,11 have Both BLM,13 and RBoth BLM have alsablished. The manablished: a RecG ′-3′ single stranded resection that exposes a free ssDNA 3′ end suitable for loading with Rad51[E. coli RecQ helicase and RecJ 5′-3′ exonuclease[The BLM protein also possesses activities it is not known to share with RecG. BLM can act in concert with EXO1 at double stranded DNA ends to cause a 5th Rad51, reminisnuclease,19. Altenuclease. BLM hasnuclease as well nuclease,23 and/onuclease. Notablynuclease-28 that nuclease and withnuclease. In contnuclease.E. coli RecG and human BLM may be functional analogs. In order to test this hypothesis and to determine the extent to which the shared biochemical activities of BLM and RecG are responsible for suppressing the functional cellular phenotypes observed in human cells lacking BLM, we reasoned that suitable expression of RecG might suppress a BLM defect. The best characterized cellular phenotype of BLM deficiency is a 10-fold elevated frequency of sister chromatid exchanges[The mechanistic similarities between BLM and RecG have led us and others to specuxchanges, thoughtxchanges. AccordiE. coli TOP10 (Invitrogen) genomic DNA with the addition of a consensus Kozak sequence[′-ggggggggatccagccaccatggctccaaaaaaaaagcgcaaagtggcgatgaaaggtcgcctg and 5′-gggggggatatcgcggccgcttacgcattcgagta (RecG sequences underlined) followed by cloning into the pCAGGS mammalian constitutive expression vector. A cryptic polyadenylation sequence in the RecG coding sequence 5′-AATAAA (AsnLys) was removed via silent mutagenesis to 5′-AACAAG (AsnLys). Carboxy-terminal additions of the enhanced green fluorescent protein (EGFP) coding sequence were constructed either to produce a RecG-EGFP fusion protein with a GSG linker peptide . The RecG expression constructs with full annotation are available from the non-profit Addgene plasmid repository (http://www.addgene.org) as plasmids #31274 and #31275.The coding sequence for RecG was isolated from sequence and the na virus,38, a VABLM+” and the cervical carcinoma line HeLa S3 (ATCC: American Type Culture Collection) “HeLa”. Cell lines used that are deficient in BLM protein include GM08505 (Coriell Cell Repositories) which are SV40 transformed fibroblasts derived from a Bloom syndrome patient homozygous for the Ashkenazi Jewish founder BLM mutation (6-bp del/7-bp ins) at nucleotide 2281 of the open reading frame, hereafter referred to as “BLM-”. A second BLM deficient line used was GM16375 (Coriell Cell Repositories) which are EBV transformed lymphocytes from a French-Canadian Bloom syndrome patient homozygous for a C>A transversion resulting in a (S595X) termination mutation, hereafter referred to as “BLM- FC”. The BLM-defective line stably suppressed by either BLM cDNA expression, or by a control empty vector are the lines PSNF5 “BLM-: cDNA” and PSNG13 “BLM-: empty vector” respectively, as described in[L-gln and antibiotic supplementation at 37C in a humidified 5% CO2 incubator.Cell lines used that express normal BLM include the SV40-transformed fibroblast line GM00637 (Coriell Cell Repositories) “ribed in  containing an expression cassette for the RecG-EGFP fusion construct . We found a significant RecG dose-dependent decrease in SCEs per chromosome in BLM- cells (Table) with the highest level of RecG expression tested reducing the elevation of SCEs by 75%. In our hands, expression of the human BLM protein from a cDNA construct in BLM- cells reduces this characteristic elevated SCE phenotype by 80% . Expression of EGFP alone without RecG in BLM- cells has no statistically significant effect on SCE levels  gradually lost EGFP expression during two months of continuous cell culture in the absence of selection, likely due to epigenetic silencing of the RecG-EGFP transgene. In the resulting “BLM-: lost RecG fuse” line, SCE levels were re-elevated to nearly those of either the parental BLM- line, or the control BLM- line containing a transgene for EGFP alone “BLM-: EGFP” . The changes to the banding pattern in the subclones relative to that of the parental clonal population represent mitotic recombination events that occurred sufficiently late in the expansion of the parental clonal population as to be undetectable as visible minor-intensity banding. The relatively small number of changes to major intensity bands in the subclones and the lack of detectable minor bands in any of the cell populations is consistent with the low levels of spontaneous gene cluster restructuring seen in other BLM+ transformed human cell lines[Expression of RecG as an independent polypeptide co-translated with EGFP did not have an obvious effect on gene cluster instability in a cell line wild-type for BLM protein Figure even tholl lines.E. coli RecG protein is able to largely, but not completely, suppress two functional human cellular phenotypes of BLM deficiency: elevated sister chromatid exchange, and elevated gene cluster instability. Although this result is in accord with the several shared biochemical activities of these two proteins, this functional suppression across different kingdoms of biology is interesting, particularly when considering that there appears to be no relationship of evolutionary sequence homology between RecG and BLM. Both RecG and BLM are members of the DEXDc superfamily of helicase proteins, and both contain both DEXDc and HELICc subdomains (FigureE. coli RecQ protein is the clear evolutionary homolog of BLM on the basis of sequence similarity within these two conserved domains. The helicase family membership of RecG notwithstanding, RecG does not primarily fulfill the classical function of a helicase but rather seems to have co-opted the molecular engine of a helicase to translocate on double stranded DNA. We suggest that this manner of translocation may also be true of BLM particularly during the branch migration of Holliday junctions since the crystal structure of a Holliday junction shows minimal single-stranded DNA character[We show here that expression of the haracter. Both ReE. coli RecG protein, with essentially no sequence similarity to human BLM, would seem unlikely to engage in any of the well-characterized protein-protein interactions that are important for function of the BLM protein in the wild-type human cellular context, although we have not experimentally ruled out these interactions. The capacity with which RecG can suppress BLM- cellular phenotypes suggests therefore that the physiological role of BLM in suppressing the two phenotype we investigated, sister chromatid exchanges and gene cluster instability, is to perform the same molecular reactions that can be performed in a human cell by the RecG monomer alone, namely direct manipulations of DNA structures. This is not to rule out a role for BLM and associated protein-protein interactions in suppression of other manifestations of genomic instability, or potentially BLM accessory proteins may help localize BLM to DNA structures upon which both BLM and RecG can act, thereby reducing the required level of BLM in the cell relative to the large amount of ectopic RecG expressed in the cell lines of this study. Activities of BLM not known to be shared by RecG, such as the unwinding of G-quadruplex DNA, must play a minor role in both sister chromatid exchange and gene cluster instability suppression assayed herein, or alternatively, a G-quadruplex activity of RecG may remain to be discovered.The E. coli and human cells respectively: they recognize stalled/regressed DNA replication forks and then utilize their common biochemical functions to mitigate this topological genomic damage. Given the well-established biochemical similarities between the two proteins and the capacity for RecG to functionally substitute for BLM shown in this work, we consider this the most parsimonious conclusion. Nevertheless, an alternative possibility consistent with our data is that the lesions recognized by BLM and RecG may be distinct from each other, but that may be converted though subsequent processing into a common form. For example, human cells, lacking RecG, may over-produce the classic substrate for RecG: a replication fork missing the nascent leading strand which may then be converted, by some as yet uncharacterized mechanism, into a bona fide distinct substrate for the BLM protein. The converse situation is also possible: that in the absence of BLM, the lesion recognized by BLM is converted into a different lesion that can be recognized and repaired by RecG. An additional possibility is that the lesion recognized by BLM and RecG may be the same, yet the two proteins may convert the lesion to different, but still less genomically destabilizing alternative structures. Mechanistic details aside, that the bacterial RecG protein can relieve human genomic instability phenotypes resulting from BLM protein deficiency demonstrates the highly conserved nature of DNA structural lesions and the type of mitigating enzymatic processing required to preserve genomic stability.We suggest that RecG and BLM fulfill the same physiological function in E. coli genomic stabilization has only recently been elucidated. In the absence of RecG, PriA initiates spurious replication forks throughout the bacterial genome, causing poorly-controlled genomic over-replication and compromised viability[BLM- cells share this over-replicated phenotype. Curiously, the E. coli RecQ protein rather than protecting the cell from aberrant recombination structures as the human BLM and E. coli RecG proteins do, seems to act instead to promote their formation[E. coli by the RecG protein, and is an example of convergent evolution.The role of BLM in human genomic stabilization is well-established. In contrast, a major mechanistic role of RecG in iability. In the iability. It willormation. Cells lormation. An analormation. One evoE. coli RecG and human BLM play similar, and to some extent interchangeable, roles in suppressing genomic instability phenotypes when expressed in human cells. Accordingly, given their lack of sequence homology, E. coli RecG and human BLM may be an example of convergent evolution.The authors declare that they have no competing interests.E. coli. AJP directed the studies and wrote the manuscript. All authors read and approved the final manuscript.MWK carried out cell line development and molecular analysis, DMS participated in gene cluster instability experiments, WAW subcloned the RecG coding sequence from


Inappropriate activity of c-Met can cause wide variety of carcinomas. c-Met inhibitor are relatively new class of small molecules that inhibit the enzymatic activity of c-Met tyrosine kinase. Met inhibitors divided into two main classes: class I (SU-11274-like) and class II (AM7-like). The use of c-Met inhibitors with other therapeutic agents could be crucial for overcoming potential resistance as well as for improving overall clinical benefit. Met pathway inhibitors might be used in combination with other treatments, including chemo-, radio- or immunotherapy It isHepatocyte growth factor (HGF) is the only known ligand of the MET receptor ,5,12. Upc-Met inhibitors are relatively new class of small molecules that inhibit the enzymatic activity of the c-Met tyrosine kinase. Pyrrole-indolinone PHA-665752) is a prototype selective class of inhibitors that inhibits HGF/SF-induced receptor phosphorylation ,5,19. Th752 is a The Met pathway is one of the most frequently dysregulated pathways in human cancer . c-Met iThe use of c-Met inhibitors with other therapeutic agents could be crucial for overcoming potential resistance as well as for improving overall clinical benefit. As a key element in the development of any targeted therapy, the biochemical and molecular determination of the precise functions of the Met pathway in the context of other relevant pro-cancer pathways will undoubtedly play a significant role in this effort . More imAuthors declare they have no competing interest.AM and HMA did manuscript drafting and AS, AMHK and SS did critical review. All have given final approval of the version to be published.


Inappropriate antibiotic use is an important factor associated with antibiotic resistance and related medical costs. These outcomes impede the effectiveness of infection prevention control programmes. Our study is to determine the prevalence of antibiotic prescription and rationale for prescribed antibiotics to hospital inpatients in Vietnam.A one-day prevalence survey in 2008 was conducted in 36 hospitals representing three different hospital levels across Vietnam. Medical records of all inpatients were reviewed to collect demographics, number and antibiotic class, and indications for antibiotic prescription. Based on the guidelines of the Association for Professionals in Infection Control and Epidemiology, USA, reasons for antibiotic use were classified into (1) identified pathogen directed, (2) empirical, or (3) prophylactic.The crude antibiotic use was 67.4% (3811/5654). Broad-spectrum antibiotics such as cephalosporins (70.3%), penicillins (21.6%), and aminoglycosides (18.9%) were most commonly used. Of antibiotic used patients, 54.7% were prescribed empirically and 30.8% were unclearly indicated. Risk factors independently associated with unclear antibiotic prescription were as follows: National level hospitals , provincial/regional hospitals , obstetrics ward , and surgical ward .Suboptimal antibiotic prescription practices are common in our participating hospitals and emphasise the necessity for evidence-based guideline to be developed and implemented in Vietnamese hospitals.None declared.


The MET proto-oncogene, encoding the tyrosine kinase receptor for Hepatocyte Growth Factor (HGF) regulates invasive growth, a genetic program that associates control of cell proliferation with invasion of the extracellular matrix and protection from apoptosis. Physiologically, invasive growth takes place during embryonic development, and, in post-natal life, in wound healing and regeneration of several tissues. The MET oncogene is overexpressed and/or genetically mutated in many tumors, thereby sustaining pathological invasive growth, a prerequisite for metastasis. MET is the subject of intense research as a target for small molecule kinase inhibitors and, together with its ligand HGF, for inhibitory antibodies. The tight interplay of MET with the protease network has unveiled mechanisms to be exploited to achieve effective inhibition of invasive growth. The MET proto-oncogene encodes the tyrosine kinase receptor for Hepatocyte Growth Factor (HGF), also known as Scatter Factor  a catalytic region, containing Tyr1234 and Tyr1235, which, upon receptor dimerization and transphosphorylation, upregulate kinase activity; (iii) a carboxy-terminal sequence including Tyr1349 and Tyr1356 that works as a multifunctional docking site required and sufficient to recruit the core of cytoplasmic signal transducers and adaptors  CD44v6, required to link the MET cytoplasmic tail to the actin cytoskeleton and, together with Gab1, to sustain activation of the MAP kinase cascade; (ii) α6β4 integrin, acting as a supplementary docking platform for amplification of PI-3 Kinase, MAP kinase, and SRC-dependent pathways; (iii) B family plexins, the receptors for semaphorins, which can trans-activate MET in the absence of HGF  MET interaction with its ligand HGF; (ii) MET receptor oligomerization; (iii) MET catalytic activity; (iv) MET downstream signaling , display specific activity against MET, and include, among the most selective and potent, PHA665752  inhibits MET, ALK, RON, AXL, and TIE2. In phase III trials, Crizotinib has shown a striking activity in NSCLC patients harboring the rare EML4-ALK translocation, leading to expression of a constitutively active ALK kinase  promoted metastatic dissemination of tumor cells to the liver. This effect was dependent on increased activity of the MET signaling pathway in the liver tissue microenvironment  induces shedding of MET and inhibition of MET signaling (Petrelli, The tyrosine kinase receptor encoded by the MET oncogene is expressed in a wide variety of tumors, where it often displays a deregulated activity that leads to pathological “invasive growth,” featuring invasion, and metastasis. Moreover, MET is expressed by endothelial cells, and can be involved in tumor angiogenesis. The connection between MET and tumor microenvironment is emphasized by the interplay with matrix proteases, such as ADAM-10, that modulate its activity. Overall, MET hyperactivation is likely to play a crucial role in tumor onset and progression. MET and its ligand HGF are attractive pharmacological targets: the ligand and the receptor extracellular domain can be blocked by antibodies, or by engineered protein antagonists, while the tyrosine kinase activity can be inhibited by small molecules. Antibodies and kinase inhibitors are currently tested in clinical trials with encouraging results.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


Accurate estimates of the size of the drug-using populations are essential for evidence-based policy making. However, drug users form a ‘hidden’ population, necessitating the use of indirect methods to estimate population sizes.+/AIDS– cases, limits the usefulness of the Belgian HIV/AIDS register as benchmark. To overcome these limitations, statistical corrections were required. In particular, Imputation by Chained Equations was used to correct for the missing risk factor information whereas stochastic mortality modelling was applied to account for the mortality among the HIV+/AIDS– cases. Monte Carlo simulation was used to obtain confidence intervals, properly reflecting the uncertainty due to random error as well as the uncertainty associated with the two statistical corrections mentioned above.The benchmark-multiplier method was applied to estimate the population size of ever injecting drug users (ever-IDUs), aged 18–64 years, in Belgium using data from the national HIV/AIDS register and from a sero-behavioral study among injecting drug users. However, missing risk factor information and absence of follow-up of the HIVIn 2010, the prevalence (/1000) of ever-IDUs was estimated to be 3.5 with 95% confidence interval . No significant time trends were observed for the period 2000–2010.To be able to estimate the ever-IDU population size using the Belgian HIV/AIDS register as benchmark, statistical corrections were required without which seriously biased estimates would result. By developing the improved methodology, Belgium is again able to provide ever-IDU population estimates, which are essential to assess the coverage of treatment and to forecast health care needs and costs. Accurate estimates of the size of the drug-using population are indispensable to govern and evaluate drug policy. They are particularly important to forecast health care needs and costs and to assess the coverage of treatment and harm reduction measures e.g.,2. HowevThe BM method is a very intuitive method, relatively easy to apply and hence, frequently used. The BM In this paper, the benchmark-multiplier (BM) method was applied to estimate the prevalence of ever injecting drug users (ever-IDUs) within the population aged 15–64 years in Belgium, 2000–10, using the HIV/AIDS register as benchmark. In Belgium, HIV-screening is widely used and all sera of which the screening test result was positive, are submitted for confirmation to one of the seven AIDS Reference Laboratories (ARLs) in Belgium. The registration results of all ARLs are then send to the national HIV/AIDS register. As the seven ARLs are the only laboratories subsidized for performing HIV confirmation tests, the Belgian HIV/AIDS register is deemed to be exhaustive and hence, constitutes a potential suitable benchmark.+/AIDS– cases. Not accounting for the mortality among these cases would result in an overestimation of the number of alive seropositive IDUs, with the bias increasing as the time since the onset of the HIV-epidemic (mid-eighties) increases. The methodology proposed in-19+/AIDSIn 2010, the prevalence  of ever injecting drug use in Belgium was estimated to be 3.5 (95% CI: 2.5-4.8), with no significant time trends being observed for the period 2000–10. Similar findings were reported by the other European countries providing time trends of the national prevalence of ever injecting drug use, i.e. Norway, Cyprus and the Czech republic. HoweverThe above mentioned results should also be regarded in the light of the assumptions underlying the BM method. Particularly, the BM estimates rely on the conditions that the benchmark is complete and that the multiplier is estimated based on a representative sample of the target population. As benchmark of the current analysis, the national HIV/AIDS register was used. Since its foundation, the Belgian HIV/AIDS register is deemed to be exhaustive as it includes the results of all Belgian laboratories subsidised for performing HIV confirmation tests. As not only AIDS cases but also HIV cases are registered, the Belgian HIV/AIDS register has the additional advantage that back-calculation methods are not needed to obtain the HIV prevalence. The multiplier was obtained from a national sero-prevalence study including 653 IDUs. Althougr = 41%) among all treatment demands as provided by the treatment demand indicator[To summarize, the current paper provides a thorough application of the BM method. Nevertheless, the use of such indirect methods inherently relies on empirically non-verifiable (but reasonable) assumptions, such as the representativeness of the multiplier. Therefore, the current estimate of the ever IDU prevalence should be complemented with estimates based on other data sources (e.g. substitution treatment register) and/or using other methods  (e.g.). For nondicator.+/AIDS– cases would nowadays results in seriously biased estimates. By developing the improved methodology, recent ever-IDU population estimates for Belgium could be obtained. These estimates are essential to monitor trends over time and to forecast health care needs and costs (e.g. for Hepatitis C treatment).As the latest estimates of the prevalence of ever-IDUs for Belgium date from 1995, obtainiThe authors declared that they have no competing interests.KB conceived and carried out the statistical analysis and drafted the paper. AS provided substantial intellectual input regarding the use of the HIV/AIDS register and critically revised the manuscript. MA provided substantial intellectual input regarding the statistical analysis and critically revised the manuscript. All authors read and approved the final manuscript.KB holds a master degree in psychology and a PhD in statistics on quantitative epidemiology. She is currently working as senior biostatistician within the research group Substance Use and Related Disorders. AS is a medical doctor and head of the HIV/AIDS register. MA is professor in biostatistics with strong interest in quantitative epidemiology.


IgG4-related disease is a new disease entity involving IgG4 in its clinical presentation and having 6 characteristic features: (1) systemic involvement; (2) solitary or multiple lesions showing diffuse or localized swelling, masses, nodules, and/or wall thickening on imaging; (3) high serum IgG4 concentration >135 mg/dL; (4) abundant infiltration of lymphoplasmacytes and IgG4-bearing plasma cells; (5) a positive response to corticosteroid therapy; and (6) complications of other IgG4-related diseases. To date, most IgG4-related diseases have been recognized as extrapancreatic lesions of autoimmune pancreatitis. This paper will discuss the utility of IgG4 as a biomarker of IgG4-related diseases, including in the diagnosis of autoimmune pancreatitis and its differentiation from pancreatic cancer, in the prediction of relapse, in the long-term follow-up of patients with autoimmune pancreatitis and normal or elevated IgG4 concentrations, and in patients with autoimmune pancreatitis and extrapancreatic lesions, as well as the role of IgG4 in the pathogenesis of IgG4-related disease. IgG4-related disease is a new disease entity involving IgG4 in its clinical presentation. To date, 6 characteristic features of IgG4-related disease have been identified: 1) systemic involvement; (2) solitary or multiple lesions showing diffuse or localized swelling, masses, nodules, and/or wall thickening on imaging; (3) high serum IgG4 concentrations >135 mg/dL; (4) abundant infiltration of lymphoplasmacytes and IgG4-bearing plasma cells; (5) a positive response to corticosteroid therapy; (6) complications of other IgG4-related diseases [ systemic IgG4-related disease involves organs throughout the entire body. The major manifestations of IgG4-related disease include autoimmune pancreatitis, lacrimal and salivary gland lesions known as Mikulicz's disease, sclerosing cholangitis, retroperitoneal fibrosis, lung disease, and tubulointerstitial nephritis. In addition, many minor lesions have been reported in patients with IgG4-related disease, including hypophysitis, thyroiditis, hepatopathy, and prostatitis. At present, it is not clear whether these lesions are caused by the same etiology or merely show clinical and pathological findings associated with IgG4. Imaging modalities have shown diffuse or localized swelling in the pancreas and the lacrimal and salivary glands, masses in patients with retroperitoneal fibrosis, nodules in patients with lung pseudotumors, and wall thickening in the bronchi and bile ducts. Most patients with IgG4-related disease have high serum IgG4 concentrations, over 135 mg/dL, . Althoug This paper will discuss the utility of serum IgG4 concentrations as a biomarker of the major IgG4-related disease, autoimmune pancreatitis. Topics will include IgG4 concentration and the diagnosis of autoimmune pancreatitis, as well as its differentiation from pancreatic cancer; IgG4 and the prediction of relapse; long-term followup of patients with autoimmune pancreatitis and either normal or elevated IgG4 concentration; IgG4 and extrapancreatic lesions in patients with autoimmune pancreatitis; and the role of IgG4 in the pathogenesis of IgG4-related disease.γ-globulins, resulting in β–γ bridging. Immunoprecipitation assays have confirmed that this band is always due to elevation of IgG4 concentration [ The sera of patients with autoimmune pancreatitis have a polyclonal band in the rapidly migrating fraction of ntration . IgG is ntration . Corticontration . The utintration –12. Diffntration  and idiontration . Clinical features of autoimmune pancreatitis have been reported to differ based on the serum concentration of IgG4. Compared with patients having normal serum IgG4 levels, those with elevated IgG4 are regarded as being in a highly active state, with a higher incidence of jaundice at onset, more frequent diffuse pancreatic enlargement on imaging, significantly higher 18F-2-fluoro-2-deoxy-d-glucose uptake by pancreatic lesions, more frequent extrapancreatic lesions, and more frequent requirement for maintenance therapy .  In addition, infiltration of IgG4 bearing plasma cells is a histological hallmark of autoimmune pancreatitis and is used in pathologic diagnoses .  Lymphoplasmacytic sclerosing pancreatitis (LPSP), which is similar pathologically to autoimmune pancreatitis, has been observed in 2.5% of patients undergoing the Whipple resection . Therefon = 26), sclerosing cholangitis (n = 18), lachrymal and salivary gland lesions (n = 5), and retroperitoneal fibrosis (n = 4). In addition, the involvement of other organs and symptoms were seen at relapse. We failed to identify any serum markers at diagnosis that could predict relapse, although we observed elevated concentrations of IgG and immune complex in the relapse compared with the nonrelapse group, although these differences were not significant. Serial changes in IgG4 and immune complexes in a 69-year-old woman with autoimmune pancreatitis who experienced 3 relapses showed that these markers were elevated in serum several months before clinically evident relapse, suggesting that regular measurements of these markers in an out-patient clinic may predict relapse [ Some patients with autoimmune pancreatitis experience relapse during their clinical course. For effective management, it is necessary to determine the frequency of relapse and its prevention. During the period from 1992 to 2011, a total of 93 patients with autoimmune pancreatitis were examined and treated at Shinshu University Hospital. Of the 84 patients followed up for more than 1 year, 28 (33%) experienced relapse. In Japanese patients, the relapse rate has been estimated to vary from 30 to 50%,  although relapse . We followed 2 patients with autoimmune pancreatitis for 10 years each, a 55-year-old man with a serum IgG4 concentration of 1135 mg/dL and a 65-year-old woman with a serum IgG4 concentration of 42 mg/dL . The fir Extrapancreatic lesions in patients with autoimmune pancreatitis may involve organs throughout the entire body , 8. Seru IgG4 in these patients may be (1) pathogenic, (2) anti-inflammatory, or (3) as a rheumatoid factor. For example, anti-desmoglein3 IgG4 autoantibody has been reported pathogenic for pemphigus vulgaris . Transfe IgG4 may act as an autoantibody against IgG or have rheumatoid factor activity. Western blotting has shown that IgG4 from the sera of patients with autoimmune pancreatitis can bind to IgG1, IgG2, IgG3, and IgG Fc . FurtherThe utility of serum IgG4 concentration as a biomarker of the major IgG4-related disease, autoimmune pancreatitis, includes its ability to diagnose autoimmune pancreatitis as well as to differentiate this disease from pancreatic cancer. Moreover, serum IgG4 concentration may be a marker for predicting relapse and for the evaluation of extrapancreatic lesions. It remains unclear, however, whether IgG4 and its rheumatoid factor-like activity may be beneficial or pathogenic in these patients.


Orbital IgG4-related disease, which can occur in adults of any age, is characterized by IgG4-positive lymphoplasmacytic infiltrations in ocular adnexal tissues. The signs and symptoms include chronic noninflammatory lid swelling and proptosis. Patients often have a history of allergic disease and elevated serum levels of IgG4 and IgE as well as hypergammaglobulinemia. Orbital IgG4-related disease must be differentiated from idiopathic orbital inflammation and ocular adnexal marginal zone B-cell lymphoma to ensure appropriate and effective treatment. Systemic steroid therapy decreases the size of the lesions, but relapse often occurs when systemic steroid therapy is discontinued. IgG4-related diseases are systemic syndromes characterized by elevated serum levels of IgG4 and IgG4-positive lymphoplasmacytic infiltrative lesions in the body. Orbital tissues are affected by IgG4-related conditions. It was first observed that Mikulicz's disease correlated with IgG4-related disease  and lateThe median age of patients with orbital IgG4-related disease is 59 years (range: 30 to 86 years) with a 1 : 1 male-to-female ratio [The signs and symptoms of orbital IgG4-related disease are chronic lid swelling  and propPatients with orbital IgG4-related disease sometimes have systemic IgG4-related lesions in their submandibular glands 29%), lymph nodes (14%), pancreas 5%), or bile ducts (5%) –5. IgG4-%, or bil%, lymph in situ [in vivo activation of the immune system by activated Th2 cells [Laboratory data of patients with orbital IgG4-related disease show elevated serum levels of IgG4 and IgE, as well as hypergammaglobulinemia –5. In coin situ . Although2 cells , 10.The histology of orbital IgG4-related disease includes different degrees of lymphoplasmacytic infiltration with dominant sclerosing lesions or reactive lymphoid follicle  mediated systemic vasculitis (such as Churg-Strauss syndrome and Wegener granulomatosis), and reactive lymphoid hyperplasia without IgG4-positive plasma cells .Idiopathic orbital inflammations and idiopathic orbital myositis have unknown etiology but involve inflammation. They are characterized by sudden onset of orbital inflammation, periocular pain, swelling and redness of the eyelids, proptosis, ptosis, and ocular motility restrictions . These din situ hybridization and immunoglobulin heavy chain gene rearrangements by southern blot analysis can differentiate between marginal zone B-cell lymphomas with IgG4-positive plasma cells and IgG4-related inflammatory disorder. Ocular adnexal lymphomas are reported to arise in IgG4-related sclerosing dacryoadenitis, indicating a possible link between the two conditions [ Ocular adnexal marginal zone B-cell lymphomas make up the majority of lymphomas arising from the ocular adnexa. They are characterized histologically by the presence of reactive follicles in up to 64% of cases, sclerosis in up to 20% of cases, and plasma cells in up to 35% of cases . These hnditions . However ANCA-related vasculitis often infiltrates in ocular adnexal lesions. The symptoms of patients with orbital lesions include periocular pain, which can differentiate these patients from those with orbital IgG4-related disease. However, the histology may be similar to that of IgG4-related disease. Thus, ANCA-related vasculitis may not only include nonspecific inflammatory lesions , but alsFinally, Mikulicz's disease includes symmetrical bilateral lacrimal gland enlargements and frequently correlates with IgG4-related disease . HoweverTreatments for patients with orbital IgG4-related diseases may include systemic steroids, radiotherapy, or rituximab –5. StudiOrbital IgG4-related disease has several unique characteristics that distinguish it from other orbital inflammatory conditions. Orbital IgG4-related disease differs from other IgG4-related diseases in the body in that it arises from nonglandular lesions and is not associated histologically with obliterative phlebitis.