Blockade of catecholamine-induced growth by adrenergic and dopaminergic receptor antagonists in Escherichia coli O157:H7, Salmonella enterica and Yersinia enterocolitica

BACKGROUND: The ability of catecholamines to stimulate bacterial growth was first demonstrated just over a decade ago. Little is still known however, concerning the nature of the putative bacterial adrenergic and/or dopaminergic receptor(s) to which catecholamines (norepinephrine, epinephrine and dopamine) may bind and exert their effects, or even whether the binding properties of such a receptor are similar between different species. RESULTS: Use of specific catecholamine receptor antagonists revealed that only α, and not β, adrenergic antagonists were capable of blocking norepinephrine and epinephrine-induced growth, while antagonism of dopamine-mediated growth was achieved with the use of a dopaminergic antagonist. Both adrenergic and dopaminergic antagonists were highly specific in their mechanism of action, which did not involve blockade of catecholamine-facilitated iron-acquisition. Use of radiolabeled norepinephrine suggested that the adrenergic antagonists could be acting by inhibiting catecholamine uptake. CONCLUSION: The present data demonstrates that the ability of a specific pathogen to respond to a particular hormone is dependent upon the host anatomical region in which the pathogen causes disease as well as the neuroanatomical specificity to which production of the particular hormone is restricted; and that both are anatomically coincidental to each other. As such, the present report suggests that pathogens with a high degree of exclusivity to the gastrointestinal tract have evolved response systems to neuroendocrine hormones such as norepinephrine and dopamine, but not epinephrine, which are found with the enteric nervous system

Estimating changes in overall survival using progression-free survival in metastatic breast and colorectal cancer

Objectives: In clinical trials of new cancer drugs, reliable data for progression-free survival will often become available far sooner than reliable data for overall survival. The aim of this study was to determine how many months it would be expected that any given new drug for metastatic breast or colorectal cancer will add to overall survival times given that the number of months the drug adds to progression-free survival times relative to a standard drug is roughly already known.Methods: A literature search was conducted over Medline for randomized controlled trials (RCTs) published between January 1980 and August 2008 that assessed the effect of a drug treatment in comparison to an alternative drug treatment on patients with either metastatic breast or metastatic colorectal cancer.Results: The literature search found 95 and 74 RCTs for metastatic breast and colorectal cancer, respectively, that satisfied the study's inclusion criteria. The results from these trials are consistent, in the case of each of these two metastatic cancers, with gains in time to disease progression being generally associated with no gains or with very slight gains or losses in post-progression survival (i.e., the time between disease progression and death).Conclusions: It would appear that drugs for metastatic breast or colorectal cancer that extend, by a given amount, the time period between the start of treatment and disease progression (i.e., time to progression) have a strong tendency to extend, by roughly the same amount, the period between the start of treatment and death (i.e., overall survival).</jats:p

Rural Transportation Planning: How to Effectively Plan, Implement, and Communicate an Access Management Study

ABSTRACT Over the past decade, states have experienced a shortage of highway funds needed to keep up with transportation growth. When this occurs, both transportation studies and construction projects are drastically cut back. In most cases, urbanized areas tend to consume the largest percent of available funds. Hardest hit for transportation study and construction funds usually are the rural areas. This makes it difficult to establish need and fiscal priorities in rural areas. The answer: Access Management becomes the most valuable transportation and land use management tool for maintaining the integrity of rural highways. Transportation planning experience shows that the neglected rural arterials of today become the over-developed suburban arterials of the future. Anticipation of transportation needs and wants of others, with an in-depth appraisal of their present highway system, helps identify how one can manage long-term growth and ensure safe and efficient transportation solutions. The U.S. Route13/Wallops Island Access Management Study, completed by the Virginia Department of Transportation in May 2002, is a successful example of such a project. The 69-mile corridor on Virginia&apos;s isolated rural eastern shore peninsula serves interstate travelers, town residents, farm equipment, tourists, bicyclists, school buses, long haul truckers and commuters. This major access study, for the Commonwealth, looked primarily at ways to make the access to the roadway safer and more efficient. Just to name a few of the concerns that had to be addressed included: the road contains more than 1,300 driveways--most without adequate turn lanes, almost 300 median crossovers, intersecting cross roads that do not line up from one side to the other, antiquated drainage culverts that can be dangerous if you happen to leave the highway, variable-width medians and numerous speed change zones. This paper will address how we effectively planned, implemented, and communicated the outcome of an access management study based on lessons learned on this very successful Virginia experience. Topics covered will include: • Performing a needs and infrastructure assessment • Using GIS for innovative data collection, design, and analysis • Effectively linking community and interagency involvement • Creating a conceptual solution using state-of-the-art graphic and techniques • Involving and informing public and private interests • Assistance localities with zoning ordinance • Developing guidelines for future access studies • Turning the plan into a reality

Evidence-based selection of training compounds for use in the mechanism-based integrated prediction of drug-induced liver injury in man

The current test systems employed by pharmaceutical industry are poorly predictive for drug-induced liver injury (DILI). The ‘MIP-DILI’ project addresses this situation by the development of innovative preclinical test systems which are both mechanism-based and of physiological, pharmacological and pathological relevance to DILI in humans. An iterative, tiered approach with respect to test compounds, test systems, bioanalysis and systems analysis is adopted to evaluate existing models and develop new models that can provide validated test systems with respect to the prediction of specific forms of DILI and further elucidation of mechanisms. An essential component of this effort is the choice of compound training set that will be used to inform refinement and/or development of new model systems that allow prediction based on knowledge of mechanisms, in a tiered fashion. In this review, we focus on the selection of MIP-DILI training compounds for mechanism-based evaluation of non-clinical prediction of DILI. The selected compounds address both hepatocellular and cholestatic DILI patterns in man, covering a broad range of pharmacologies and chemistries, and taking into account available data on potential DILI mechanisms (e.g. mitochondrial injury, reactive metabolites, biliary transport inhibition, and immune responses). Known mechanisms by which these compounds are believed to cause liver injury have been described, where many if not all drugs in this review appear to exhibit multiple toxicological mechanisms. Thus, the training compounds selection offered a valuable tool to profile DILI mechanisms and to interrogate existing and novel in vitro systems for the prediction of human DILI

Effects on heart pumping function when using foam and gauze for negative pressure wound therapy of sternotomy wounds

<p>Abstract</p> <p>Background</p> <p>Negative pressure wound therapy (NPWT) has remarkable effects on the healing of poststernotomy mediastinitis. Foam is presently the material of choice for NPWT in this indication. There is now increasing interest in using gauze, as this has proven successful in the treatment of peripheral wounds. It is important to determine the effects of NPWT using gauze on heart pumping function before it can be used for deep sternotomy wounds. The aim was to examine the effects of NPWT when using gauze and foam on the heart pumping function during the treatment of a sternotomy wound.</p> <p>Methods</p> <p>Eight pigs underwent median sternotomy followed by NPWT at -40, -70, -120 and -160 mmHg, using foam or gauze. The heart frequency, cardiac output, mean systemic arterial pressure, mean pulmonary artery pressure, central venous pressure and left atrial pressure were recorded.</p> <p>Results</p> <p>Cardiac output was not affected by NPWT using gauze or foam. Heart frequency decreased during NPWT when using foam, but not gauze. Treatment with foam also lowered the central venous pressure and the left atrial pressure, while gauze had no such effects. Mean systemic arterial pressure, mean pulmonary artery pressure and systemic vascular resistance were not affected by NPWT. Similar haemodynamic effects were observed at all levels of negative pressure studied.</p> <p>Conclusions</p> <p>NPWT using foam results in decreased heart frequency and lower right and left atrial filling pressures. The use of gauze in NPWT did not affect the haemodynamic parameters studied. Gauze may thus provide an alternative to foam for NPWT of sternotomy wounds.</p

Internet-Based Photoaging Within Australian Pharmacies to Promote Smoking Cessation: Randomized Controlled Trial

Background: Tobacco smoking leads to death or disability and a drain on national resources. The literature suggests that cigarette smoking continues to be a major modifiable risk factor for a variety of diseases and that smokers aged 18-30 years are relatively resistant to antismoking messages due to their widely held belief that they will not be lifelong smokers. Objective: To conduct a randomized controlled trial (RCT) of a computer-generated photoaging intervention to promote smoking cessation among young adult smokers within a community pharmacy setting. Methods: A trial was designed with 80% power based on the effect size observed in a published pilot study; 160 subjects were recruited (80 allocated to the control group and 80 to the intervention group) from 8 metropolitan community pharmacies located around Perth city center in Western Australia. All participants received standardized smoking cessation advice. The intervention group participants were also digitally photoaged by using the Internet-based APRIL Face Aging software so they could preview images of themselves as a lifelong smoker and as a nonsmoker. Due to the nature of the intervention, the participants and researcher could not be blinded to the study. The main outcome measure was quit attempts at 6-month follow-up, both self-reported and biochemically validated through testing for carbon monoxide (CO), and nicotine dependence assessed via the Fagerström scale.Results: At 6-month follow-up, 5 of 80 control group participants (6.3%) suggested they had quit smoking, but only 1 of 80 control group participants (1.3%) consented to, and was confirmed by, CO validation. In the intervention group, 22 of 80 participants (27.5%) reported quitting, with 11 of 80 participants (13.8%) confirmed by CO testing. This difference in biochemically confirmed quit attempts was statistically significant (χ21=9.0, P=.003). A repeated measures analysis suggested the average intervention group smoking dependence score had also significantly dropped compared to control participants (P<.001). These differences remained statistically significant after adjustment for small differences in gender distribution and nicotine dependence between the groups. The mean cost of implementing the intervention was estimated at AU $5.79 per participant. The incremental cost-effectiveness ratio was AU$46 per additional quitter. The mean cost that participants indicated they were willing to pay for the digital aging service was AU $20.25 (SD 15.32). Conclusions: Demonstrating the detrimental effects on facial physical appearance by using a computer-generated simulation may be both effective and cost-effective at persuading young adult smokers to quit

The realistic performance achievable with mycobacterial automated culture systems in high and low prevalence settings

<p>Abstract</p> <p>Background</p> <p>Diagnostic tests are generally used in situations with similar pre-test probability of disease to where they were developed. When these tests are applied in situations with very different pre-test probabilities of disease, it is informative to model the likely implications of known characteristics of test performance in the new situation. This is the case for automated <it>Mycobacterium tuberculosis </it>(MTB) liquid culture systems for tuberculosis case detection which were developed and are widely used in low burden settings but are only beginning to be applied on a large scale in high burden settings.</p> <p>Methods</p> <p>Here we model the performance of MTB liquid culture systems in high and low tuberculosis (TB) prevalence settings using detailed published data concentrating on the likely frequency of cross-contamination events.</p> <p>Results</p> <p>Our model predicts that as the TB prevalence in the suspect population increases there is an exponential increase in the risk of MTB cross-contamination events expected in otherwise negative samples, even with equivalent technical performance of the laboratories. Quality control and strict cross-contamination measures become increasingly critical as the burden of MTB infection among TB suspects increases. Even under optimal conditions the realistically achievable specificity of these systems in high burden settings will likely be significantly below that obtained in low TB burden laboratories.</p> <p>Conclusions</p> <p>Liquid culture systems can play a valuable role in TB case detection in laboratories in high burden settings, but laboratory workers, policy makers and clinicians should be aware of the increased risks, independent of laboratory proficiency, of cross-contamination events in high burden settings.</p

Comparative Cost-Effectiveness Analysis of Two MSF Surgical Trauma Centers

INTRODUCTION: There is a dearth of data on cost-effectiveness of surgical care in resource-poor countries. Doctors Without Borders (Médecins Sans Frontières; MSF) is a nongovernmental organization (NGO) involved in the many facets of health care for underserved populations, including surgical care. METHODS: A cost-effectiveness analysis (CEA) was attempted at two of their surgical trauma hospitals: Teme Hospital in Nigeria and La Trinité Hospital in Haiti. CONCLUSION: At $172 and$223 per Disability-Adjusted Life-Year (DALY) averted, respectively, they are in line with other reported CEAs for surgical and nonsurgical activities in similar contexts

Challenges of Meeting Surgical Needs in the Developing World

The burden of surgical conditions and diseases is increasing in low-income and middle-income countries, but the capacity to meet the demands they present is not following pace. Ongoing initiatives, such as brief visits by surgeons from advantaged countries, sending surgical residents to spend time in a developing country as part of their training, or ships weighing anchor offshore and offering some limited on-shore or on-board services, have not proven successful. More comprehensive and sustainable solutions include the development of local training programs, better retention of trainees with adequate incentives particularly in rural areas, and engaging government and professional associations, as well as academic institutions, to develop and implement policies to address local training needs