Evolving resistance among Gram-positive pathogens.

Antimicrobial therapy is a key component of modern medical practice and a cornerstone for the development of complex clinical interventions in critically ill patients. Unfortunately, the increasing problem of antimicrobial resistance is now recognized as a major public health threat jeopardizing the care of thousands of patients worldwide. Gram-positive pathogens exhibit an immense genetic repertoire to adapt and develop resistance to virtually all antimicrobials clinically available. As more molecules become available to treat resistant gram-positive infections, resistance emerges as an evolutionary response. Thus, antimicrobial resistance has to be envisaged as an evolving phenomenon that demands constant surveillance and continuous efforts to identify emerging mechanisms of resistance to optimize the use of antibiotics and create strategies to circumvent this problem. Here, we will provide a broad perspective on the clinical aspects of antibiotic resistance in relevant gram-positive pathogens with emphasis on the mechanistic strategies used by these organisms to avoid being killed by commonly used antimicrobial agents.

A liaR deletion restores susceptibility to daptomycin and antimicrobial peptides in multidrug-resistant Enterococcus faecalis.

Daptomycin is a lipopeptide antibiotic that is used clinically against many gram-positive bacterial pathogens and is considered a key frontline bactericidal antibiotic to treat multidrug-resistant enterococci. Emergence of daptomycin resistance during therapy of serious enterococcal infections is a major clinical issue. In this work, we show that deletion of the gene encoding the response regulator, LiaR (a member of the LiaFSR system that controls cell envelope homeostasis), from daptomycin-resistant Enterococcus faecalis not only reversed resistance to 2 clinically available cell membrane-targeting antimicrobials (daptomycin and telavancin), but also resulted in hypersusceptibility to these antibiotics and to a variety of antimicrobial peptides of diverse origin and with different mechanisms of action. The changes in susceptibility to these antibiotics and antimicrobial peptides correlated with in vivo attenuation in a Caenorhabditis elegans model. Mechanistically, deletion of liaR altered the localization of cardiolipin microdomains in the cell membrane. Our findings suggest that LiaR is a master regulator of the enterococcal cell membrane response to diverse antimicrobial agents and peptides; as such, LiaR represents a novel target to restore the activity of clinically useful antimicrobials against these organisms and, potentially, increase susceptibility to endogenous antimicrobial peptides.

Candida infective endocarditis: an observational cohort study with a focus on therapy

Candida infective endocarditis is a rare disease with a high mortality rate. Our understanding of this infection is derived from case series, case reports, and small prospective cohorts. The purpose of this study was to evaluate the clinical features and use of different antifungal treatment regimens for Candida infective endocarditis. This prospective cohort study was based on 70 cases of Candida infective endocarditis from the International Collaboration on Endocarditis (ICE)-Prospective Cohort Study and ICE-Plus databases collected between 2000 and 2010. The majority of infections were acquired nosocomially (67%). Congestive heart failure (24%), prosthetic heart valve (46%), and previous infective endocarditis (26%) were common comorbidities. Overall mortality was high, with 36% mortality in the hospital and 59% at 1 year. On univariate analysis, older age, heart failure at baseline, persistent candidemia, nosocomial acquisition, heart failure as a complication, and intracardiac abscess were associated with higher mortality. Mortality was not affected by use of surgical therapy or choice of antifungal agent. A subgroup analysis was performed on 33 patients for whom specific antifungal therapy information was available. In this subgroup, 11 patients received amphotericin B-based therapy and 14 received echinocandin-based therapy. Despite a higher percentage of older patients and nosocomial infection in the echinocandin group, mortality rates were similar between the two groups. In conclusion, Candida infective endocarditis is associated with a high mortality rate that was not impacted by choice of antifungal therapy or by adjunctive surgical intervention. Additionally, echinocandin therapy was as effective as amphotericin B-based therapy in the small subgroup analysis.

Failure of high-dose daptomycin for bacteremia caused by daptomycin-susceptible Enterococcus faecium harboring LiaSR substitutions.

High-dose daptomycin (DAP) therapy failed in a neutropenic patient with bloodstream infection caused by a DAP-susceptible Enterococcus faecium (minimum inhibitory concentration, 3 µg/mL) harboring genetic changes associated with DAP resistance, with persistent bacteremia and selection of additional resistances. Daptomycin monotherapy should be used cautiously against DAP-susceptible E. faecium strains with minimum inhibitory concentrations >2 µg/mL.

Observations of increased tropical rainfall preceded by air passage over forests.

Vegetation affects precipitation patterns by mediating moisture, energy and trace-gas fluxes between the surface and atmosphere. When forests are replaced by pasture or crops, evapotranspiration of moisture from soil and vegetation is often diminished, leading to reduced atmospheric humidity and potentially suppressing precipitation. Climate models predict that large-scale tropical deforestation causes reduced regional precipitation, although the magnitude of the effect is model and resolution dependent. In contrast, observational studies have linked deforestation to increased precipitation locally but have been unable to explore the impact of large-scale deforestation. Here we use satellite remote-sensing data of tropical precipitation and vegetation, combined with simulated atmospheric transport patterns, to assess the pan-tropical effect of forests on tropical rainfall. We find that for more than 60 per cent of the tropical land surface (latitudes 30 degrees south to 30 degrees north), air that has passed over extensive vegetation in the preceding few days produces at least twice as much rain as air that has passed over little vegetation. We demonstrate that this empirical correlation is consistent with evapotranspiration maintaining atmospheric moisture in air that passes over extensive vegetation. We combine these empirical relationships with current trends of Amazonian deforestation to estimate reductions of 12 and 21 per cent in wet-season and dry-season precipitation respectively across the Amazon basin by 2050, due to less-efficient moisture recycling. Our observation-based results complement similar estimates from climate models, in which the physical mechanisms and feedbacks at work could be explored in more detail.

Response to steroid therapy in autism secondary to autoimmune lymphoproliferative syndrome.

We report a child who developed autoimmune lymphoproliferative syndrome (ALPS) secondary to a heterozygous dominant negative mutation in the death domain of the Fas receptor. Previously developmentally normal, he had symptoms of autism with rapid regression in developmental milestones coincident with the onset of lymphoproliferation and autoimmune hemolytic anemia. Low-dose steroid therapy induced early and complete remission in the ALPS phenotype. There was subjective improvement, followed by objective improvement in speech and developmental milestones. We propose that autism may be part of the autoimmune disease spectrum of ALPS in this child, and this case represents a novel manifestation and target organ involvement in this disease.

Serum autoantibodies to brain in Landau-Kleffner variant, autism, and other neurologic disorders.

OBJECTIVE: Etiologically unexplained disorders of language and social development have often been reported to improve in patients treated with immune-modulating regimens. Here we determined the frequency of autoantibodies to brain among such children. DESIGN: We collected sera from a cohort of children with (1) pure Landau-Kleffner syndrome (n = 2), (2) Landau-Kleffner syndrome variant (LKSV, n = 11), and (3) autistic spectrum disorder (ASD, n = 11). None had received immune-modulating treatment before the serum sample was obtained. Control sera (n = 71) were from 29 healthy children, 22 with non-neurologic illnesses (NNIs), and 20 children with other neurologic disorders (ONDs). We identified brain autoantibodies by immunostaining of human temporal cortex and antinuclear autoantibodies using commercially available kits. RESULTS: IgG anti-brain autoantibodies were present in 45% of sera from children with LKSV, 27% with ASD, and 10% with ONDs compared with 2% from healthy children and control children with NNIs. IgM autoantibodies were present in 36% of sera from children with ASD, 9% with LKSV, and 15% with ONDs compared with 0% of control sera. Labeling studies identified one antigenic target to be endothelial cells. Antinuclear antibodies with titers >/=1:80 were more common in children with ASD and control children with ONDs. CONCLUSION: Children with LKSV and ASD have a greater frequency of serum antibodies to brain endothelial cells and to nuclei than children with NNIs or healthy children. The presence of these antibodies raises the possibility that autoimmunity plays a role in the pathogenesis of language and social developmental abnormalities in a subset of children with these disorders.

Claves ilustradas para las subfamilias, tribus y géneros de esfécidos neotropicales (Apoidea: Sphecidae) / Illustrated keys to genera, tribes, and subfamilies of neotropical sphecidae (Apoidea: Sphecidae)

141 genera of Sphecidae, representing 1,628 species, are known from the Neotropical Region. Illustrated keys to genera, tribes, and subfamilies are presented in Spanish and English. These have been modified and updated from those in Bohart & Menke's 1976 book, Sphecid Wasps of the World. The validity of a few genera recognized by Bohart & Menke is now in question and the keys are annotated to alert users to these problems. A list of neotropical genera and higher taxa is included. Names in the list are appended with significant literature published since 1976. The history and current status of subfamilies are reviewed. Ten subfamilies are recognized. Family characters and biology are summarized. morphological terms are illustrated and a glossary provided

Substance use among the mentally ill: prevalence, reasons for use, and effects on illness.

Substance use among a random sample of mentally ill, community-based patients was examined. Current use was found to have declined substantially from a high lifetime prevalence, and a family history of substance abuse was associated with moderate to heavy use. No association was found between heavy substance use and elevated psychopathology, hospitalization, or medication noncompliance. Hospital admissions and some symptoms were less prevalent among users preferring marijuana.

Changes in the food intake and body weight of protein-malnourished rats infected with Nippostrongylus brasiliensis (Nematoda).

The daily food intake and related changes in body weight were measured in young rats which were fed on synthetic diets containing 1% (3 experiments), 2% (4 experiments) and 20% (1 experiment) casein respectively. Some rats were infected with Nippostrongylus brasiliensis and allowed to feed ad libitum, some remained uninfected and were allowed to feed ad libitum, while others, which were matched by initial weight with rats from the infected group, remained uninfected and were given only the same amount of food as that consumed during the previous 24 h by their infected partners. No significant differences were detected between the rats before the start of the infection. Thereafter, the food intake of the infected undernourished rats was usually found to be significantly lower and the loss of body weight significantly greater than those of the uninfected rats. In infection periods of relatively long duration, the pair-fed uninfected rats did not lose as much weight as their infected partners even though their food intake (1% and 2% casein) was the same. Although the food intake, and consequently the weight, of infected rats fed on the diet containing 20% casein were significantly less than in their uninfected partners, no significant differences were observed between the weights of the infected and pair-fed rats fed on this diet.