The plexin C1 receptor promotes acute inflammation

Acute inflammation is the pathophysiological basis of important clinical conditions associated with organ failure. The initial inflammatory response is controlled by the chemokine system, yet recent data have indicated that the neuronal guidance cues are significantly involved in the orchestration of this process. Previous work has shown the proinflammatory capacity of the guidance cue semaphorin (Sema) 7a, but the role of one of its target receptors, the plexin C1 (PLXNC1) receptor is to date unknown. We report here that PLXNC1 is expressed outside the nervous system and induced during acute inflammation. PLXNC1^?/? mice with C57BL/6 background demonstrated decreased inflammatory responses during zymosan A (ZyA)‐induced peritonitis. Subsequent in vivo studies revealed altered rolling, adhesion, and transmigration properties of PLXNC1^?/? leukocytes. Blockade of PLXNC1 was associated with attenuated chemotactic transendothelial migration properties in vitro. Studies in chimeric mice revealed that hematopoietic PLXNC1^?/? animals demonstrated an attenuated inflammatory response. To probe the therapeutic potential of PLXNC1 we treated C57BL/6 WT mice with an anti‐PLXNC1 antibody and a PLXNC1 binding peptide. Both of these interventions significantly dampened ZyA‐induced peritonitis. These results implicate an important role of PLXNC1 during an acute inflammatory response and indicate PLXNC1 as a potential target for the control of conditions associated with acute inflammation.     

ImmPort: disseminating data to the public for the future of immunology

The immunology database and analysis portal (ImmPort) system is the archival repository and dissemination vehicle for clinical and molecular datasets created by research consortia funded by the National Institute of Allergy and Infectious Diseases Division of Allergy, Immunology, and Transplantation. With nearly 100 datasets now publicly available and hundreds of downloads per month, ImmPort is an important source for raw data and protocols from clinical trials, mechanistic studies, and novel methods for cellular and molecular measurements. To facilitate data transfer, templates for data representation and standard operating procedures have also been created and are also publicly available. ImmPort facilitates transparency and reproducibility in immunology research, serves as an important resource for education, and enables newly generated hypotheses and data-driven science.     

Metabolic Syndrome,Diabetes, and Cardiovascular Risk in HIV

HIV infection and its treatment have been associated with adipose tissue changes and disorders of glucose and lipid metabolism. The proportion of HIV-infected adults over the age of 50 is also growing placing HIV-infected adults at particular risk for metabolic perturbations and cardiovascular disease. The metabolic syndrome in HIV-infected adults has been increasingly studied but whether HIV is associated with greater risk remains unclear, likely because of the interplay of host, viral and antiretroviral factors that are associated with the components of the metabolic syndrome. The relationship between HIV and diabetes mellitus (DM) risk has also been debated. While the Framingham Risk Score is a well-accepted measure of 10-year cardiovascular risk in the general population, it may not accurately predict risk in the HIV setting due to HIV-related factors such as inflammation that are not accounted for. We summarize the recent literature on metabolic syndrome, DM, and cardiovascular risk in HIV-infected adults.     

Yersinia pseudotuberculosis Efficiently Escapes Polymorphonuclear Neutrophils during Early Infection

The human-pathogenic species of the Gram-negative genus Yersinia preferentially target and inactivate cells of the innate immune defense, suggesting that this is a critical step by which these bacteria avoid elimination and cause disease. In this study, bacterial interactions with dendritic cells, macrophages, and polymorphonuclear neutrophils (PMNs) in intestinal lymphoid tissues during early Yersinia pseudotuberculosis infection were analyzed. Wild-type bacteria were shown to interact mainly with dendritic cells, but not with PMNs, on day 1 postinfection, while avirulent yopH and yopE mutants interacted with PMNs as well as with dendritic cells. To unravel the role of PMNs during the early phase of infection, we depleted mice of PMNs by using an anti-Ly6G antibody, after which we could see more-efficient initial colonization by the wild-type strain as well as by yopH, yopE, and yopK mutants on day 1 postinfection. Dissemination of yopH, yopE, and yopK mutants from the intestinal compartments to mesenteric lymph nodes was faster in PMN-depleted mice than in undepleted mice, emphasizing the importance of effective targeting of PMNs by these Yersinia outer proteins (Yops). In conclusion, escape from interaction with PMNs due to the action of YopH, YopE, and YopK is a key feature of pathogenic Yersinia species that allows colonization and effective dissemination.     

Evaluation of real-time PCR versus PCR with liquid-phase hybridization for detection of enterovirus RNA in cerebrospinal fluid

A LightCycler and two TaqMan real-time PCR assays were evaluated against an older PCR with liquid-phase hybridization method for the detection of enterovirus RNA in 74 patient samples. The two-step LightCycler and the two-step TaqMan formats correlated well with each other (r(2) = 0.90) and were equally sensitive compared to the liquid-phase hybridization method, whereas the one-step recombinant Tth DNA polymerase format was rather insensitive, detecting enterovirus RNA in only about one-half of those patient samples previously positive by liquid-phase hybridization. The two-step TaqMan method was optimized utilizing 10 micro l of cDNA and demonstrated the highest degree of analytical sensitivity among the methods evaluated in our study, being able to reproducibly quantify down to 510 copies of enteroviral RNA/ml of cerebrospinal fluid. This new assay can be performed in 4 h, is much less labor intensive, and showed less cross-reactivity with rhinovirus than the liquid-phase hybridization assay. Thus, the two-step TaqMan assay should prove useful in the diagnosis of enteroviral meningitis versus bacterial meningitis, thereby resulting in timely and appropriate clinical management that can amount to significant cost savings to the patient and health care system.     

Performance and views of examiners in the Applied Knowledge Test for the nMRCGP licensing examination

Background

A new computer-based Applied Knowledge Test (AKT) has been developed for the licensing examination for general practice administered by the Royal College of General Practitioners.

Aim

The aim of this evaluation was to assess the acceptability, feasibility, and validity of the test as well as its transfer to a computerised format at local test centres.

Design of study

Computer-based test and postal questionnaire.

Participants and setting

Panel of examiners, Membership of the Royal College of General Practitioners (MRCGP) examination, UK.

Method

Self-administered postal questionnaires were sent to examiners not involved with the development of the test after completing it. Their performance scores were compared with those of candidates.

Results

The majority of participants (80.9%) were satisfied with the new computer-based test. Responses relating to content and attitudes to the test were also positive overall, but some problems with content were highlighted. Fewer examiners (61.9%) were positive about the physical comfort of the test centre, including seating, heating, and lighting. Examiners had significantly higher scores (mean 83.3%, range 69 to 93%, 95% confidence interval [CI] = 81.9 to 84.7%) than ‘real’ candidates (mean 75.0%, range 45 to 94%, 95% CI = 74.6 to 75.5%), who subsequently took an identical test.

Conclusion

The new computer-based licensing test (the AKT) was found to be acceptable to the majority of examiners. The pass–fail standard, determined by routine methods including an Angoff procedure, was supported by the higher success rate of examiners compared with candidates. The use of selected groups to assess high-stakes (licensing) examinations can be useful for assessing test validity.     

Effects of Exercise Training in Patients with Chronic Heart Failure and Sleep Apnea

Study Objectives:

To test the effects of exercise training on sleep and neurovascular control in patients with systolic heart failure with and without sleep disordered breathing.

Design:

Prospective interventional study.

Setting:

Cardiac rehabilitation and exercise physiology unit and sleep laboratory.

Patients:

Twenty-five patients with heart failure, aged 42 to 70 years, and New York Heart Association Functional Class I-III were divided into 1 of 3 groups: obstructive sleep apnea (n = 8), central sleep apnea (n = 9) and no sleep apnea (n = 7).

Interventions:

Four months of no-training (control) followed by 4 months of an exercise training program (three 60-minute, supervised, exercise sessions per week).

Measures and Results:

Sleep (polysomnography), microneurography, forearm blood flow (plethysmography), peak VO_2, and quality of life were evaluated at baseline and at the end of the control and trained periods. No significant changes occurred in the control period. Exercise training reduced muscle sympathetic nerve activity (P < 0.001) and increased forearm blood flow (P < 0.01), peak VO₂(P < 0.01), and quality of life (P < 0.01) in all groups, independent of the presence of sleep apnea. Exercise training improved the apnea-hypopnea index, minimum O₂ saturation, and amount stage 3-4 sleep (P < 0.05) in patients with obstructive sleep apnea but had no significant effects in patients with central sleep apnea.

Conclusions.

The beneficial effects of exercise training on neurovascular function, functional capacity, and quality of life in patients with systolic dysfunction and heart failure occurs independently of sleep disordered breathing. Exercise training lessens the severity of obstructive sleep apnea but does not affect central sleep apnea in patients with heart failure and sleep disordered breathing.

Citation:

Ueno LM; Drager LF; Rodrigues ACT; Rondon MUPB; Braga AMFW; Mathias W; Krieger EM; Barretto ACP; Middlekauff HR; Lorenzi-Filho G; Negrão CE. Effects of exercise training in patients with chronic heart failure and sleep apnea. SLEEP 2009;32(5):637-647.     

Vancomycin MICs for Staphylococcus aureus Vary by Detection Method and Have Subtly Increased in a Pediatric Population Since 2005

Vancomycin MICs for Staphylococcus aureus isolates in a pediatric hospital with a high rate of staphylococcal infections were examined for any increase over a 7-year period. A broth microdilution scheme allowed direct comparison of the MICs generated by this method to MICs generated by Etest. MICs generated by both methods were determined with the same inoculum suspension. One hundred sixty-five S. aureus isolates were selected on the basis of the patients having been bacteremic or having received vancomycin as the definitive therapy for their infections. Of the 165 isolates, 117 were methicillin-resistant S. aureus and 48 were methicillin-susceptible S. aureus. Forty-seven were acquired in the hospital (nosocomial), 56 were community acquired, and 62 were community onset-health care associated. All but one isolate tested by broth microdilution had MICs of <1.0 μg/ml, while 96% of these same isolates tested by Etest had MICs of ≥1 μg/ml. A significant increase in MICs that occurred after study year 4 (2004 to 2005) was demonstrated by the Etest (P < 0.00007) but not by broth microdilution. MICs were not different for isolates of community or health care origin, regardless of methodology. The proportion of isolates with Etest MICs of <1 and ≥1 μg/ml between children with bacteremia for ≤5 days and >5 days (P = 0.3) was not different. We conclude that MICs for pediatric isolates have increased slightly since 2005 and therapeutic decisions based on vancomycin MICs need to be made by considering the methodology used.Recent studies have reported a steady increase in vancomycin MICs for Staphylococcus aureus that may be, in part, due to the increase in the use of vancomycin in response to community-acquired (CA) methicillin-resistant S. aureus (MRSA) (18). Also, some studies report that vancomycin MICs between 1.5 and 2.0 μg/ml are predictors of a poor therapeutic response in adults (15). The decrease in vancomycin susceptibility is difficult to assess by percentage reporting because the MIC increases are subtle, would all be classified as susceptible by using 2009 Clinical and Laboratory Standards Institute (CLSI) interpretive breakpoints, and are only detected by using a more closely spaced (arithmetic) dilution scheme versus the standard geometric dilution scheme (16). We report the first study of vancomycin MIC trends for S. aureus isolates from children comparing Etest and modified broth microdilution (BMD) schemes.