Structural Interventions in Heart Failure: Mending a Broken Heart.

Advanced heart failure is often accompanied by perturbations in cardiac chamber or valve geometries which result in worsening cardiac function and hemodynamics. Once limited to surgical procedures, recent developments in minimally invasive percutaneous techniques have demonstrated efficacy in patients with both reduced and preserved ejection fraction who are at an elevated surgical risk for perioperative events. This review highlights a subset of the interventions available in clinical practice or in development for the treatment of these valvular and structural alterations.

Serotonin syndrome following left ventricular assist device implantation: A report and institution-specific strategy for prevention.

Serotonin syndrome is a potentially lethal complication of antidepressant therapy. Cardiac surgical patients are at particularly high risk of serotonin syndrome due to the prevalence of depression in patients with advanced cardiac disease, many of whom receive multiple serotonergic agents in the perioperative period. Here, we describe a case of postoperative serotonin syndrome following methylene blue administration for perioperative vasoplegia during left ventricular assist device implantation. We additionally describe an institution-specific strategy to minimize future occurrences of serotonin syndrome in this high-risk population. .

"Quorum Non-Sensing": Social Cheating and Deception in Vibrio cholerae.

Quorum sensing (QS) is widely used by bacteria to coordinate behavior in response to external stimuli. In Vibrio cholerae, this process is important for environmental survival and pathogenesis, though, intriguingly, a large percentage of natural isolates are QS deficient. Here, we show that QS-deficient mutants can spread as social cheaters by ceasing production of extracellular proteases under conditions requiring their growth. We further show that mutants stimulate biofilm formation and are over-represented in biofilms compared to planktonic communities; on this basis, we suggest that QS-deficient mutants may have the side effect of enhancing environmental tolerance of natural populations due to the inherent resistance properties of biofilms. Interestingly, high frequencies of QS-deficient individuals did not impact production of QS signaling molecules despite mutants being unable to respond to these inducers, indicating that these variants actively cheat by false signaling under conditions requiring QS. Taken together, our results suggest that social cheating may drive QS deficiency emergence within V. cholerae natural populations.

Clostridium difficile contains plasmalogen species of phospholipids and glycolipids.

Analysis of the polar lipids of many pathogenic and non-pathogenic clostridia has revealed the presence of plasmalogens, alk-1'-enyl ether-containing phospholipids and glycolipids. An exception to this finding so far has been Clostridium difficile, an important human pathogen which is the cause of antibiotic-associated diarrhea and other more serious complications. We have examined the polar lipids of three strains of C. difficile by thin-layer chromatography and have found acid-labile polar lipids indicative of the presence of plasmalogens. The lipids from one of these strains were subjected to further analysis by liquid chromatography coupled to electrospray ionization-mass spectrometry (LC/ESI-MS), which revealed the presence of phosphatidylglycerol, cardiolipin, monohexosyldiradylglycerol, dihexosyldiradylglycerol, and two unusual glycolipids identified as an aminohexosyl-hexosyldiradylglycerol, and a trihexosyldiradylglycerol. High resolution tandem mass spectrometry determined that monohexosyldiradylglycerol, cardiolipin and phosphatidylglycerol contained significant amounts of plasmalogens. C. difficile thus joins the growing list of clostridia that have plasmalogens. Since plasmalogens in clostridia are formed by an anaerobic pathway distinct from those in animal cells, their formation represents a potential novel target for antibiotic action.

A high-throughput small-molecule screen to identify a novel chemical inhibitor of Clostridium difficile.

Clostridium difficile, a highly drug-resistant Gram-positive, spore-forming bacterium, remains a leading cause of hospital-acquired diarrhoea and antibiotic-associated colitis. Clinically, only a handful of antibiotics are used for treating C. difficile infection (CDI), suggesting a necessity for the development of new treatment options. Here we performed a high-throughput screen of 2000 drug-like compounds for inhibition of C. difficile. From this screen, one compound, 5-nitro-1,10-phenanthroline (5-NP), showed potent bactericidal effects in vitro. In addition, this compound displayed high potency towards other Clostridium spp. as well as Mycobacterium bovis but not towards other tested Gram-positive and Gram-negative bacteria. Furthermore, we show that this inhibition may proceed through a metal chelation-dependent mechanism. More importantly, preliminary evidence suggests moderate efficacy for this compound in treating CDI in a murine infection model. These results present a possible basis for the further development of this compound as an antibiotic treatment for CDI.

Applying reversible mutations of nodulation and nitrogen-fixation genes to study social cheating in Rhizobium etli-legume interaction.

Mutualisms are common in nature, though these symbioses can be quite permeable to cheaters in situations where one individual parasitizes the other by discontinuing cooperation yet still exploits the benefits of the partnership. In the Rhizobium-legume system, there are two separate contexts, namely nodulation and nitrogen fixation processes, by which resident Rhizobium individuals can benefit by cheating. Here, we constructed reversible and irreversible mutations in key nodulation and nitrogen-fixation pathways of Rhizobium etli and compared their interaction with plant hosts Phaseolus vulgaris to that of wild type. We show that R. etli reversible mutants deficient in nodulation factor production are capable of intra-specific cheating, wherein mutants exploit other Rhizobium individuals capable of producing these factors. Similarly, we show that R. etli mutants are also capable of cheating inter-specifically, colonizing the host legume yet contributing nothing to the partnership in terms of nitrogen fixation. Our findings indicate that cheating is possible in both of these frameworks, seemingly without damaging the stability of the mutualism itself. These results may potentially help explain observations suggesting that legume plants are commonly infected by multiple bacterial lineages during the nodulation process.

Role of a TehA homolog in Vibrio cholerae C6706 antibiotic resistance and intestinal colonization.

Vibrio cholerae is the causative agent of the devastating diarrheal disease cholera. A number of regulatory pathways are involved in V. cholerae pathogenesis and antibiotic resistance. For example, there are over 40 LysR-family proteins in the V. cholerae genome, but most of their functions are unknown. In this study, we examine the role of VC2323 (TehAVc) and its divergently transcribed LysR-family regulator VC2324 (TehRVc) in V. cholerae pathogenesis. We found that in V. cholerae C6706, the expression of tehAVc is dependent on TehRVc. VC2323 (TehAVc), homologous to the Escherichia coli tellurite resistance protein (TehAEc), differs from TehAEc in that TehAVc has no noticeable role in tellurite resistance but instead contributes to chloramphenicol resistance. Interestingly, both tehAVc and tehRVc mutants were defective in colonization of infant mice. Though the expression of a key virulence gene tcpA was not affected in either of these mutants, tehAVc mutants failed to attach to mouse intestinal surfaces in the presence of crude bile, suggesting a new role of the TehAVc-TehRVc pair in V. cholerae pathogenesis.

LysR family activator-regulated major facilitator superfamily transporters are involved in Vibrio cholerae antimicrobial compound resistance and intestinal colonisation.

Expression of a multidrug resistance transporter renders bacterial cells resistant to a variety of drugs. The major facilitator superfamily (MFS) comprises the largest group of bacterial multidrug transporters. There are over 20 MFS efflux pumps annotated on the genome of Vibrio cholerae, but little is known about their functions and regulation. In this study, five MFS efflux pumps were characterised, each of which is associated with a divergently transcribed putative LysR-type transcriptional regulator (MfsR). It was found that each of these MFS structural genes is regulated by the corresponding MfsR regulator. Deletion of these five mfs genes results in increased susceptibility to tetracycline and crude bile as well as a colonisation defect in an infant mouse colonisation model. Moreover, tetracycline and unknown intestinal signals could serve as co-inducers for the MfsR regulators. These data suggest that MFS efflux pumps are important both for antimicrobial resistance and V. cholerae pathogenesis.