Showing papers in "Upsala Journal of Medical Sciences in 2014"
TL;DR: A brief overview of environmental exposure routes of antibiotics is provided to provide some thoughts about the current knowledge of the associated risks for humans as well as ecosystems, and management options to reduce risks are indicated.
Abstract: Molecules with antibiotic properties, produced by various microbes, have been around long before mankind recognized their usefulness in preventing and treating bacterial infections. Bacteria have therefore been exposed to selection pressures from antibiotics for very long times, however, generally only on a micro-scale within the immediate vicinity of the antibiotic-producing organisms. In the twentieth century we began mass-producing antibiotics, mainly synthetic derivatives of naturally produced antibiotic molecules, but also a few entirely synthetic compounds. As a consequence, entire bacterial communities became exposed to unprecedented antibiotic selection pressures, which in turn led to the rapid resistance development we are facing today among many pathogens. We are, rightly, concerned about the direct selection pressures of antibiotics on the microbial communities that reside in or on our bodies. However, other environments, outside of our bodies, may also be exposed to antibiotics through different routes, most often unintentionally. There are concerns that increased selection pressures from antibiotics in the environment can contribute to the recruitment of resistance factors from the environmental resistome to human pathogens. This paper attempts to 1) provide a brief overview of environmental exposure routes of antibiotics, 2) provide some thoughts about our current knowledge of the associated risks for humans as well as ecosystems, and 3) indicate management options to reduce risks.
221 citations
TL;DR: High demands on resources for the construction of phage libraries and the testing of individual phages mean the effectiveness and host range must be characterized, and immunological risks must be assessed for every single phage.
Abstract: The rise of antibiotic-resistant bacterial strains, causing intractable infections, has resulted in an increased interest in phage therapy. Phage therapy preceded antibiotic treatment against bacterial infections and involves the use of bacteriophages, bacterial viruses, to fight bacteria. Virulent phages are abundant and have proven to be very effective in vitro, where they in most cases lyse any bacteria within the hour. Clinical trials on animals and humans show promising results but also that the treatments are not completely effective. This is partly due to the studies being carried out with few phages, and with limited experimental groups, but also the fact that phage therapy has limitations in vivo. Phages are large compared with small antibiotic molecules, and each phage can only infect one or a few bacterial strains. A very large number of different phages are needed to treat infections as these are caused by genetically different strains of bacteria. Phages are effective only if enough of them can reach the bacteria and increase in number in situ. Taken together, this entails high demands on resources for the construction of phage libraries and the testing of individual phages. The effectiveness and host range must be characterized, and immunological risks must be assessed for every single phage.
163 citations
TL;DR: Resistant mutants selected at low antibiotic concentrations are generally more fit than those selected at high concentrations but can still be highly resistant.
Abstract: Human use of antibiotics has driven the selective enrichment of pathogenic bacteria resistant to clinically used drugs. Traditionally, the selection of resistance has been considered to occur mainly at high, therapeutic levels of antibiotics, but we are now beginning to understand better the importance of selection of resistance at low levels of antibiotics. The concentration of an antibiotic varies in different body compartments during treatment, and low concentrations of antibiotics are found in sewage water, soils, and many water environments due to natural production and contamination from human activities. Selection of resistance at non-lethal antibiotic concentrations (below the wild-type minimum inhibitory concentration) occurs due to differences in growth rate at the particular antibiotic concentration between cells with different tolerance levels to the antibiotic. The minimum selective concentration for a particular antibiotic is reached when its reducing effect on growth of the susceptible strain balances the reducing effect (fitness cost) of the resistance determinant in the resistant strain. Recent studies have shown that resistant bacteria can be selected at concentrations several hundred-fold below the lethal concentrations for susceptible cells. Resistant mutants selected at low antibiotic concentrations are generally more fit than those selected at high concentrations but can still be highly resistant. The characteristics of selection at low antibiotic concentrations, the potential clinical problems of this mode of selection, and potential solutions will be discussed.
149 citations
TL;DR: Examples that illustrate the possible impact of resistance on animal health and consequences thereof are discussed and the need to preserve the efficacy of currently available antibiotics through antibiotic stewardship is emphasized.
Abstract: Most of the literature on the consequences of emergence and spread of bacteria resistant to antibiotics among animals relate to the potential impact on public health. But antibiotics are used to treat sick animals, and resistance in animal pathogens may lead to therapy failure. This has received little scientific attention, and therefore, in this article, we discuss examples that illustrate the possible impact of resistance on animal health and consequences thereof. For all animals, there may be a negative effect on health and welfare when diseases cannot be treated. Other consequences will vary depending on why and how different animal species are kept. Animals kept as companions or for sports often receive advanced care, and antibiotic resistance can lead to negative social and economic consequences for the owners. Further, spread of hospital-acquired infections can have an economic impact on the affected premises. As to animals kept for food production, antibiotics are not needed to promote growth, but, if infectious diseases cannot be treated when they occur, this can have a negative effect on the productivity and economy of affected businesses. Antibiotic resistance in animal bacteria can also have positive consequences by creating incentives for adoption of alternative regimes for treatment and prevention. It is probable that new antibiotic classes placed on the market in the future will not reach veterinary medicine, which further emphasizes the need to preserve the efficacy of currently available antibiotics through antibiotic stewardship. A cornerstone in this work is prevention, as healthy animals do not need antibiotics.
139 citations
TL;DR: It is proposed that the emergence and spread of antibiotic resistance can only be understood in a multi-parameter space, and measuring the effect on antibiotic resistance of parameters such as contact rates, transfer rates, integration rates, replication rates, diversification rates, and selection rates will allow for a better prediction of antibiotics resistance and possibilities of focused interventions.
Abstract: The emergence and spread of antibiotic resistance among human pathogens is a relevant problem for human health and one of the few evolution processes amenable to experimental studies. In the present review, we discuss some basic aspects of antibiotic resistance, including mechanisms of resistance, origin of resistance genes, and bottlenecks that modulate the acquisition and spread of antibiotic resistance among human pathogens. In addition, we analyse several parameters that modulate the evolution landscape of antibiotic resistance. Learning why some resistance mechanisms emerge but do not evolve after a first burst, whereas others can spread over the entire world very rapidly, mimicking a chain reaction, is important for predicting the evolution, and relevance for human health, of a given mechanism of resistance. Because of this, we propose that the emergence and spread of antibiotic resistance can only be understood in a multi-parameter space. Measuring the effect on antibiotic resistance of parameters such as contact rates, transfer rates, integration rates, replication rates, diversification rates, and selection rates, for different genes and organisms, growing under different conditions in distinct ecosystems, will allow for a better prediction of antibiotic resistance and possibilities of focused interventions.
137 citations
TL;DR: Propofol anaesthesia might be better in surgery for some cancer types, but the retrospective design of this study, with uneven distributions of several confounders, distorted the picture and emphasize the need for a randomized controlled trial.
Abstract: Background. Commonly used inhalational hypnotics, such as sevoflurane, are pro-inflammatory, whereas the intravenously administered hypnotic agent propofol is anti-inflammatory and anti-oxidative. A few clinical studies have indicated similar effects in patients. We examined the possible association between patient survival after radical cancer surgery and the use of sevoflurane or propofol anaesthesia.Patients and methods. Demographic, anaesthetic, and surgical data from 2,838 patients registered for surgery for breast, colon, or rectal cancers were included in a database. This was record-linked to regional clinical quality registers. Cumulative 1- and 5-year overall survival rates were assessed using the Kaplan–Meier method, and estimates were compared between patients given propofol (n = 903) or sevoflurane (n = 1,935). In a second step, Cox proportional hazard models were calculated to assess the risk of death adjusted for potential effect modifiers and confounders.Results. Differences in over...
135 citations
TL;DR: Through further studies of the spatial and temporal distribution of resistant bacteria in wild birds, it can better assess their role and thereby help to mitigate the increasing global problem of antibiotic resistance.
Abstract: Wild birds have been postulated as sentinels, reservoirs, and potential spreaders of antibiotic resistance. Antibiotic-resistant bacteria have been isolated from a multitude of wild bird species. Several studies strongly indicate transmission of resistant bacteria from human rest products to wild birds. There is evidence suggesting that wild birds can spread resistant bacteria through migration and that resistant bacteria can be transmitted from birds to humans and vice versa. Through further studies of the spatial and temporal distribution of resistant bacteria in wild birds, we can better assess their role and thereby help to mitigate the increasing global problem of antibiotic resistance.
120 citations
TL;DR: It is concluded that lumbar spinal stenosis quite frequently may be a consequence of SSA and that further studies are warranted.
Abstract: Background.Senile systemic amyloidosis (SSA) derived from wild-type transthyretin is a fairly common condition of old individuals, particularly men. The main presentation is by cardiac involvement, ...
120 citations
TL;DR: In vitro data suggest that combinations can be effective even if the bacteria are resistant to the individual antibiotics, although existing evidence is insufficient to support the choice of combinations and explain the synergistic effects observed.
Abstract: Combination antibiotic therapy for Gram-negative sepsis is controversial. The present review provides a brief summary of the existing knowledge on combination therapy for severe infections with multidrug-resistant Pseudomonas spp., Acinetobacter spp., and Enterobacteriaceae. Empirical combination antibiotic therapy is recommended for severe sepsis and septic shock to reduce mortality related to inappropriate antibiotic treatment. Because definitive combination therapy has not been proven superior to monotherapy in meta-analyses, it is generally advised to de-escalate antibiotic therapy when the antibiotic susceptibility profile is known, although it cannot be excluded that some subgroups of patients might still benefit from continued combination therapy. Definitive combination therapy is recommended for carbapenemase-producing Enterobacteriaceae and should also be considered for severe infections with Pseudomonas and Acinetobacter spp. when beta-lactams cannot be used. Because resistance to broad-spectrum beta-lactams is increasing in Gram-negative bacteria and because no new antibiotics are expected to become available in the near future, the antibacterial potential of combination therapy should be further explored. In vitro data suggest that combinations can be effective even if the bacteria are resistant to the individual antibiotics, although existing evidence is insufficient to support the choice of combinations and explain the synergistic effects observed. In vitro models can be used to screen for effective combinations that can later be validated in animal or clinical studies. Further, in the absence of clinical evidence, in vitro data might be useful in supporting therapeutic decisions for severe infections with multidrug-resistant Gram-negative bacteria.
118 citations
TL;DR: The need to create a well-funded antibiotic discovery and development pipeline that can sustain the continuous delivery of novel candidate drugs into clinical trials is emphasized, to ensure the maintenance of the advanced medical procedures the authors currently take for granted.
Abstract: Antibiotics are the medical wonder of our age, but an increasing frequency of resistance among key pathogens is rendering them less effective. If this trend continues the consequences for cancer patients, organ transplant patients, and indeed the general community could be disastrous. The problem is complex, involving abuse and overuse of antibiotics (selecting for an increasing frequency of resistant bacteria), together with a lack of investment in discovery and development (resulting in an almost dry drug development pipeline). Remedial approaches to the problem should include taking measures to reduce the selective pressures for resistance development, and taking measures to incentivize renewed investment in antibiotic discovery and development. Bringing new antibiotics to the clinic is critical because this is currently the only realistic therapy that can ensure the level of infection control required for many medical procedures. Here we outline the complex process involved in taking a potential novel antibiotic from the initial discovery of a hit molecule, through lead and candidate drug development, up to its entry into phase I clinical trials. The stringent criteria that a successful drug must meet, balancing high efficacy in vivo against a broad spectrum of pathogens, with minimal liabilities against human targets, explain why even with sufficient investment this process is prone to a high failure rate. This emphasizes the need to create a well-funded antibiotic discovery and development pipeline that can sustain the continuous delivery of novel candidate drugs into clinical trials, to ensure the maintenance of the advanced medical procedures we currently take for granted.
95 citations
TL;DR: Situations where human behaviour is involved in relation to antibiotics, focusing on providers and consumers are addressed, and ‘antibiotic mainstreaming' is implemented as a potentially effective way for behaviour modification, i.e. to address consequences for maintaining effective antibiotics in all activities and decisions in society.
Abstract: This paper addresses: 1) Situations where human behaviour is involved in relation to antibiotics, focusing on providers and consumers; 2) Theories about human behaviour and factors influencing behaviour in relation to antibiotics; 3) How behaviour in relation to antibiotics can change; and, 4) Antibiotic mainstreaming as an approach to facilitate changes in human behaviour as regards antibiotics. Influencing human behaviour in relation to antibiotics is a complex process which includes factors like knowledge, attitudes, social norms, socio-economic conditions, peer pressure, experiences, and bio-physical and sociobehavioural environment. Further, key concepts are often perceived in different ways by different individuals. While designing and implementing projects or programmes for behavioural change with respect to antibiotics for professionals or consumers it is helpful to consider theories or models of behaviour change, e.g. the ‘stages of change model’, including pre-contemplation, contemplation, preparation, action, and maintenance. People in different stages of change are susceptible to different behaviour modification strategies. Application of marketing principles to ‘global good’, so-called ‘social marketing’ ,t o improve ‘welfare of the individual and society’ is gaining increased attention in public health. In conclusion, just providing correct knowledge is not sufficient although it is a pre-requisite for behaviour modification in the desired direction. We can never change the behaviour of any other human, but we can facilitate for others to change their own behaviour. One possibility is to implement ‘antibiotic mainstreaming’ as a potentially effective way for behaviour modification, i.e. to address consequences for maintaining effective antibiotics in all activities and decisions in society.
TL;DR: Down-regulation of miR-146a is related to HCC carcinogenesis and deterioration of HCC, and it is therefore a potential prognostic biomarker for HCC patients.
Abstract: Background. Aberrant expression of microRNA-146a (miR-146a) has been found in several classes of cancers. However, its expression and clinicopathological contribution in hepatocellular carcinoma (HCC) has not been fully elucidated. Objective. To explore the clinicopathological significance of the miR-146a level in HCC formalin-fixed paraffin-embedded (FFPE) tissue. Methods. Eighty-five HCC samples and their para-cancerous normal liver tissues were collected. Total mRNA including miRNA was extracted, and miR-146a expression was determined using real-time RT-PCR. Furthermore, the correlation between the miR-146a expression and clinicopathological parameters was investigated. Results. MicroRNA-146a expression in HCC tissues was lower compared with that in adjacent non-cancerous hepatic tissues. MicroRNA-146a expression was also related to clinical TNM stage, metastasis, portal vein tumor embolus, and number of tumor nodes. Conclusions. Down-regulation of miR-146a is related to HCC carcinogenesis and deterioration of HCC. MicroRNA-146a may act as a suppressor miRNA of HCC, and it is therefore a potential prognostic biomarker for HCC patients.
TL;DR: This work analyzes emergence of antibiotic resistance based on interdependencies between health systems resources and goes beyond the health system building blocks, to look at determinants of antibiotics resistance referring to wider global dynamics.
Abstract: Current use, misuse, and overuse of antibiotics raise dangers and ethical dilemmas that cannot be solved in isolation, exclusively within a health system building block or even within the health sector only. There is a need to tackle antibiotic resistance emergence and containment on levels ranging from individuals, households, and the communities, to health care facilities, the entire health sector, and finally to national and global levels. We analyse emergence of antibiotic resistance based on interdependencies between health systems resources. We further go beyond the health system building blocks, to look at determinants of antibiotic resistance referring to wider global dynamics. Multi-level governance is the key for successful action in containment strategies. This will involve, in a comprehensive way, patients, health facilities where they receive care, health systems to which these facilities pertain, and the wider national context as well as the global community that influences the funct...
TL;DR: Together with the European Medicines Agency (EMA), EUCAST determines breakpoints for existing and new antibacterial and antifungal agents and has developed a disk diffusion antimicrobial susceptibility testing method which is now, together with the new European breakpoints, being implemented in many countries both inside and outside Europe.
Abstract: Antimicrobial susceptibility testing with phenotypic methods requires breakpoints, i.e. a minimum inhibitory concentration (MIC) categorizing micro-organisms into susceptible, intermediately susceptible, and resistant for the relevant antimicrobial agent. Determinations of breakpoints require tools such as the understanding of dosing, MIC distributions of organisms without resistance mechanisms, pharmacokinetics, pharmacodynamics, and of clinical outcome in defined clinical situations. Several European countries (France, Germany, Norway, Sweden, the Netherlands, and UK), have national breakpoint committees, often with 20–30 years of experience and tradition. These committees now co-operate under the umbrella of the European Committee on Antimicrobial Susceptibility Testing (EUCAST), organized by The European Society of Clinical Microbiology and Infectious Diseases (ESCMID) and the European Centre for Disease Prevention and Control (ECDC). Together with the European Medicines Agency (EMA), EUCAST determines breakpoints for existing and new antibacterial and antifungal agents. Moreover, EUCAST has developed a disk diffusion antimicrobial susceptibility testing method which is now, together with the new European breakpoints, being implemented in many countries both inside and outside Europe.
TL;DR: The current understanding of the concepts of reversibility of antibiotic resistance and the interventions performed in hospitals and in the community are reviewed.
Abstract: Although theoretically attractive, the reversibility of resistance has proven difficult in practice, even though antibiotic resistance mechanisms induce a fitness cost to the bacterium. Associated resistance to other antibiotics and compensatory mutations seem to ameliorate the effect of antibiotic interventions in the community. In this paper the current understanding of the concepts of reversibility of antibiotic resistance and the interventions performed in hospitals and in the community are reviewed.
TL;DR: Although compelling experimental and clinical evidence supports the notion that the PDGF receptor pathway is a driver in GBM, formal proof is still missing, aPDGF receptor profile may be a biomarker for a subgroup of GBM originating from a PDGF receptors-responsive cell.
Abstract: The platelet-derived growth factor (PDGF) family of mitogens exerts vital functions during embryonal development, e.g. in the central nervous system, where PDGF drives the proliferation of oligodendrocyte precursors. PDGF and PDGF receptors are co-expressed in human glioblastoma (GBM). Whether an aberrant activation of the PDGF receptor pathway is a driving force in glioma development has remained an open question. In experimental animals, overexpression of PDGF has convincingly been shown to induce tumors, both in wild-type animals (marmoset, rat, mouse) and in mice with targeted deletions of suppressor genes, e.g. Tp53 or Ink4A. Targeting the PDGF receptor in tumor-bearing mice leads to growth inhibition and reversion of the transformed phenotype. Findings of PDGF receptor amplification or mutations in human GBM are strong indicators of a causative role of the PDGF receptor pathway. However, clinical trials using PDGF receptor antagonists have been disappointing. In conclusion, a PDGF receptor profile may be a biomarker for a subgroup of GBM originating from a PDGF receptor-responsive cell. Although compelling experimental and clinical evidence supports the notion that the PDGF receptor pathway is a driver in GBM, formal proof is still missing.
TL;DR: The new business model for antibiotic innovation should apply the 3Rs strategy for encouraging collaborative approaches to R&D in innovating novel antibiotics: sharing resources, risks, and rewards.
Abstract: The increase in antibiotic resistance and the dearth of novel antibiotics have become a growing concern among policy-makers. A combination of financial, scientific, and regulatory challenges poses barriers to antibiotic innovation. However, each of these three challenges provides an opportunity to develop pathways for new business models to bring novel antibiotics to market. Pull-incentives that pay for the outputs of research and development (R&D) and push-incentives that pay for the inputs of R&D can be used to increase innovation for antibiotics. Financial incentives might be structured to promote delinkage of a company’s return on investment from revenues of antibiotics. This delinkage strategy might not only increase innovation, but also reinforce rational use of antibiotics. Regulatory approval, however, should not and need not compromise safety and efficacy standards to bring antibiotics with novel mechanisms of action to market. Instead regulatory agencies could encourage development of companion diagnostics, test antibiotic combinations in parallel, and pool and make transparent clinical trial data to lower R&D costs. A tax on non-human use of antibiotics might also create a disincentive for non-therapeutic use of these drugs. Finally, the new business model for antibiotic innovation should apply the 3Rs strategy for encouraging collaborative approaches to R&D in innovating novel antibiotics: sharing resources, risks, and rewards.
TL;DR: Compared with conventional ventilation, after correction for obesity, this ventilation strategy reduced the area of postoperative atelectasis in one of the intervention groups but not in the other group, which included a higher proportion of smokers.
Abstract: Background. Atelectasis is common during and after general anaesthesia. We hypothesized that a ventilation strategy, without recruitment manoeuvres, using a combination of continuous positive airway pressure (CPAP) or positive end-expiratory pressure (PEEP) and a reduced end-expiratory oxygen fraction (FETO2) before ending mask ventilation with CPAP after extubation would reduce the area of postoperative atelectasis.Methods. Thirty patients were randomized into three groups. During induction and emergence, inspiratory oxygen fractions (FIO2) were 1.0 in the control group and 1.0 or 0.8 in the intervention groups. No CPAP/PEEP was used in the control group, whereas CPAP/PEEP of 6 cmH2O was used in the intervention groups. After extubation, FIO2 was set to 0.30 in the intervention groups and CPAP was applied, aiming at FETO2 < 0.30. Atelectasis was studied by computed tomography 25 min postoperatively.Results. The median area of atelectasis was 5.2 cm2 (range 1.6–12.2 cm2) and 8.5 cm2 (3–23.1 cm2) i...
TL;DR: The data suggested that perioperative blood transfusion of more than 3 units of RBCs is an independent risk factor for POCD in aged patients following total hip replacement surgery.
Abstract: Introduction. Accumulating evidence suggests that enhanced inflammatory responses contribute to the pathogenesis of postoperative cognitive dysfunction (POCD). Blood transfusion can trigger an enhancement of acute inflammatory responses. Therefore, we hypothesized that perioperative blood transfusion is associated with a higher risk of POCD in aged patients following total hip replacement surgery.Material and methods. Patients older than 65 years undergoing elective total hip replacement surgery were enrolled from October 2011 to December 2012. Neurocognitive tests were evaluated at baseline and at 7 d after surgery by a Mini-Mental State Test. Multivariate logistic regression analysis was used to determine risk factors associated with POCD.Results. Fifty-six patients (27.3%) developed POCD 7 d postoperatively. Patients who developed POCD were older, had a lower education level and preoperative hemoglobin concentration, had more blood loss, and had a lower body weight (p < 0.05). Patients with POC...
TL;DR: A step-wise approach which defines achievable aims, objectives, and milestones will succeed to produce a sustainable system of international co-operative surveillance of ABR to help define the objectives, scale, scope, and structure of possible future efforts.
Abstract: The need for global data about the scale of antibiotic resistance (ABR) in a geographical explicit and timely manner has been identified by many stakeholders, including the World Health Organization. This primer should help defining the objectives, scale, scope, and structure of possible future efforts. Stakeholders and their expected information demands were identified to generate an inventory of surveillance objectives. For simplification, an original approach was chosen to bundle sets of objectives that represent common demands and can be addressed by common subject areas, which fall into three areas. Subject area I addresses clinical demands and focuses on patients; subject area II addresses public health demands by focusing on meta-populations; subject area III addresses infection control demands and focuses on pathogens. A division into these areas leads to a separation of surveillance activities suggesting a modular approach which can provide complementary information. Moreover, the modules...
TL;DR: Handled mice displayed less variability than non-handled mice, suggesting that by using a controlled handling protocol prior to the experiments fewer C57BL/6 mice would be needed to achieve statistically significant differences in studies of learning and spatial memory using MWM.
Abstract: Background. The handling of experimental animals prior to experimental interventions is often poorly described, even though it may affect the final functional outcome. This study explores how the use of repeated handling of C57BL/6 mice prior to Morris water maze (MWM) tests can affect the performance. Methods and materials. The handled animals were subjected to the escalating handling protocol, with the investigator spending 5 min per day per cage for 8 days prior to the MWM test. On the last days of handling, the mice were introduced to water and the concept of a hidden platform. The MWM test consisted of four daily trials for 90 s per day for 4 days with a hidden platform. A probe test was performed 4 days after the last learning trial. Control animals were not handled prior to MWM. Results. Handling reduced the latency to find the platform on the first 2 days of the MWM tests and reduced thigmotaxis. The mice increased their swim speed and elicited more explorative behavior in the learning tr...
TL;DR: Constructing a sustainable yet accessible model of antibiotic distribution for LMICs is a task of health system-wide proportions, which is why it is strongly suggest using systems thinking in future research on this issue.
Abstract: The increasing antibiotic resistance is a global threat to health care as we know it. Yet there is no model of distribution ready for a new antibiotic that balances access against excessive or inappropriate use in rural settings in low- and middle-income countries (LMICs) where the burden of communicable diseases is high and access to quality health care is low. Departing from a hypothetical scenario of rising antibiotic resistance among pneumococci, 11 stakeholders in the health systems of various LMICs were interviewed one-on-one to give their view on how a new effective antibiotic should be distributed to balance access against the risk of inappropriate use. Transcripts were subjected to qualitative ‘framework’ analysis. The analysis resulted in four main themes: Barriers to rational access to antibiotics; balancing access and excess; learning from other communicable diseases; and a system-wide intervention. The tension between access to antibiotics and rational use stems from shortcomings found in the health systems of LMICs. Constructing a sustainable yet accessible model of antibiotic distribution for LMICs is a task of health system-wide proportions, which is why we strongly suggest using systems thinking in future research on this issue.
TL;DR: Overexpression of FOXM1 was overexpressed in NPC and C666-1 cells compared with normal nasopharyngeal tissues and NP69 cells and was associated with lymph node metastasis and advanced tumor stage.
Abstract: Background. The forkhead box M1 (FOXM1) transcription factor plays an important role in the metastases of many cancers. Down-regulation of FOXM1 by its inhibitor, thiostrepton, can inhibit the metastatic potential of some cancers; however, there are few studies regarding the functional significance of FOXM1 and thiostrepton in the metastases of nasopharyngeal carcinoma (NPC) and the underlying mechanism.Methods. Expression of FOXM1 in NPC, normal nasopharyngeal tissues, a NPC cell line (C666-1), and a nasopharyngeal epithelial cell line (NP69) was investigated by immunohistochemical staining, qRT-PCR, and Western blot. The correlation between FOXM1 expression and the clinical characteristics of patients was analyzed. Moreover, the effects of thiostrepton on expression of FOXM1 in C666-1 and NP69 cells, and the invasion and migration ability of C666-1 cells were examined. The expressions of MMP-2, MMP-9, fascin-1, ezrin, and paxillin were determined after treatment with thiostrepton.Results. FOXM1 w...
TL;DR: Evidence-based actions to improve antibiotic use and to slow down the problem of antibiotic resistance need to be strengthened.
Abstract: Background. The aim of this paper was to describe and analyze the effect of antibiotic policy changes on antibiotic consumption in Swedish hospitals and to review antibiotic stewardship in Swedish hospitals. Results. The main findings were: 1) Antibiotic consumption has significantly increased in Swedish hospitals over the last decade. The consumption of cephalosporins has decreased, whereas that of most other drugs including piperacillin-tazobactam, carbapenems, and penicillinase-sensitive and -resistant penicillins has increased and replaced cephalosporins. 2) Invasive infections caused by ESBL-producing Escherichia coli and Klebsiella pneumoniae have increased, but the proportion of pathogens resistant to third-generation cephalosporins causing invasive infections is still very low in a European and international perspective. Furthermore, the following gaps in knowledge were identified: 1) lack of national, regional, and local data on the incidence of antibiotic resistance among bacteria causi...
TL;DR: Securing access to effective antibiotics for current and future generations and whose responsibility is Whose responsibility?
Abstract: Securing access to effective antibiotics for current and future generations. Whose responsibility?
TL;DR: Pretreatment with intravenous DEX 1 µg/kg 5 min prior to injection of long-chain triglyceride Propofol is effective and safe in reducing the incidence and severity of pain due to propofol injection.
Abstract: Objective. The incidence of propofol injection pain during induction of general anesthesia varies from 28% to 90%. This prospective, randomized, double-blind, placebo-controlled study evaluated the effect of dexmedetomidine (DEX) for reducing the incidence and severity of propofol injection pain.Methods. Patients undergoing elective surgical procedures were randomly allocated into seven groups of 30 patients each. Experimental treatments were intravenously administered over 10 min (total volume 10 mL) prior to intravenous propofol injection, as follows: group I, the control group, was given isotonic saline. Patients in groups II, III, and IV received DEX 0.25 µg/kg, 0.5 µg/kg, or 1.0 µg/kg, respectively, mixed with isotonic saline immediately before propofol injection. Patients in groups V, VI, and VII received DEX as above, but 5 minutes before propofol injection. Propofol consisted of 1% long-chain triglyceride propofol (2.5 mg/kg) injected at 1 mL/s.Results. Median propofol injection pain score...
TL;DR: In this paper, researcher interviews have complemented literature studies to delve deeper into the specifics of the different scientific and structural barriers, and some potential solutions are offered.
Abstract: Antibiotic resistance is becoming an increasing threat, with too few novel antibiotics coming to market to replace those lost due to resistance development. Efforts by the pharmaceutical industry to screen for and design novel antibacterials have not been successful, with several companies minimizing or closing down their antibacterial research units, leading to a loss of skills and know-how. At the same time, antibiotic innovation in academia is not filling the void due to misaligned incentive structures and lack of vital knowledge of drug discovery. The scientific and structural difficulties in discovering new antibiotics have only begun to be appreciated in the latest years. Part of the problem has been a paradigm shift within both industry and academia to focus on 'rational' drug development with an emphasis on single targets and high-throughput screening of large chemical libraries, which may not be suited to target bacteria. The very particular aspects of 'targeting an organism inside another organism' have not been given enough attention. In this paper, researcher interviews have complemented literature studies to delve deeper into the specifics of the different scientific and structural barriers, and some potential solutions are offered.
TL;DR: Targeting the resistance mechanism itself by a vaccine is an interesting but hitherto unexplored approach forspread of antibiotic resistance.
Abstract: Spread of antibiotic resistance is mediated by clonal lineages of bacteria that besides being resistant also possess other properties promoting their success. Some vaccines already in use, such as the pneumococcal conjugate vaccines, have had an effect on these successful clones, but at the same time have allowed for the expansion and resistance evolution of previously minor clones not covered by the vaccine. Since resistance frequently is horizontally transferred it will be difficult to generate a vaccine that covers all possible genetic lineages prone to develop resistance unless the vaccine target(s) is absolutely necessary for spread and/or disease development. Targeting the resistance mechanism itself by a vaccine is an interesting but hitherto unexplored approach.
TL;DR: It is suggested that activation of adenosine receptors improves renal antioxidant capacity in diabetic Wistar but not SHR rats, although it improves glucose metabolism in both strains.
Abstract: Background. Diabetes and hypertension independently contribute to renal injury, and the major mechanisms involved are increased reactive oxygen species (ROS) bioavailability and renin-angiotensin system (RAS) activation. We investigated the role of adenosine in controlling ROS production and RAS activation associated with renal dysfunction in hypertension and diabetes. Methods. Fourteen days after induction of diabetes with streptozotocin in 12-week-old male Wistar and spontaneously hypertensive (SHR) rats, animals were treated during 7 days with 2-chloroadenosine (CADO group, 5 mg/kg/d), a stable analogue of adenosine, or underwent a sham operation procedure. At the end of the study (day 21), intra-arterial systolic blood pressure (SBP) was measured, and 24-h urine and plasma samples and renal tissue were collected. Results. CADO treatment decreased the plasma glucose concentration and glucose and protein excretion by more than 30% in both strains. CADO treatment decreased SBP in diabetic SHR ra...
TL;DR: The prevalence of aspirin resistance is comparable in diabetic and non-diabetic patients and hypercholesterolemia is the only independent predictor of aspirin Resistance in diabetic patients.
Abstract: Background. Diabetic patients exhibit platelet hyperreactivity, which renders them resistant to antithrombotic treatments. We aimed to investigate the prevalence and predictors of aspirin resistance in diabetic patients. Material and methods. A total of 93 diabetic and 37 non-diabetic participants were included into the study. Aspirin resistance was measured with a whole-blood desktop platelet function analyzer (PFA-100) with an epinephrine agonist. Results. Altogether 41.9% patients with DM were aspirin non-responders. Aspirin resistance was observed in 43.2% of nondiabetic patients (p = 0.89). Presence of diabetes mellitus had no effect on aspirin response (RR 0.95 (95% CI 0.44–2.05), p = 0.89) in the whole study population. Hypercholesterolemia was the only predictor of aspirin resistance in multivariate analysis in diabetic patients (RR 3.09 (95% CI 1.17–8.16), p = 0.023). Conclusion. The prevalence of aspirin resistance is comparable in diabetic and non-diabetic patients. Hypercholesterolemia is the only independent predictor of aspirin resistance in diabetic patients.