Trends in susceptibility of vancomycin-resistant Enterococcus faecium to tigecycline, daptomycin, and linezolid and molecular epidemiology of the isolates: results from the Tigecycline In Vitro Surveillance in Taiwan (TIST) study, 2006 to 2010

Among the 219 vancomycin-resistant Enterococcus faecium isolates collected in 20 Taiwanese hospitals from 2006 to 2010, all were susceptible to linezolid and daptomycin, and 98.6% were susceptible to tigecycline. There was a shift toward higher tigecycline MIC values (MIC(90)s) from 2006-2007 (0.06 μg/ml) to 2008-2010 (0.12 μg/ml). The MIC(90)s of daptomycin and linezolid remained stationary. Although pulsotypes among the isolates from the 20 hospitals varied, intrahospital spreading of several clones was identified in 13 hospitals.     

MCM4 mutation causes adrenal failure, short stature, and natural killer cell deficiency in humans

An interesting variant of familial glucocorticoid deficiency (FGD), an autosomal recessive form of adrenal failure, exists in a genetically isolated Irish population. In addition to hypocortisolemia, affected children show signs of growth failure, increased chromosomal breakage, and NK cell deficiency. Targeted exome sequencing in 8 patients identified a variant (c.71-1insG) in minichromosome maintenance-deficient 4 (MCM4) that was predicted to result in a severely truncated protein (p.Pro24ArgfsX4). Western blotting of patient samples revealed that the major 96-kDa isoform present in unaffected human controls was absent, while the presence of the minor 85-kDa isoform was preserved. Interestingly, histological studies with Mcm4-depleted mice showed grossly abnormal adrenal morphology that was characterized by non-steroidogenic GATA4- and Gli1-positive cells within the steroidogenic cortex, which reduced the number of steroidogenic cells in the zona fasciculata of the adrenal cortex. Since MCM4 is one part of a MCM2-7 complex recently confirmed as the replicative helicase essential for normal DNA replication and genome stability in all eukaryotes, it is possible that our patients may have an increased risk of neoplastic change. In summary, we have identified what we believe to be the first human mutation in MCM4 and have shown that it is associated with adrenal insufficiency, short stature, and NK cell deficiency.     

Mouse and computational models link Mlc2v dephosphorylation to altered myosin kinetics in early cardiac disease

Actin-myosin interactions provide the driving force underlying each heartbeat. The current view is that actin-bound regulatory proteins play a dominant role in the activation of calcium-dependent cardiac muscle contraction. In contrast, the relevance and nature of regulation by myosin regulatory proteins (for example, myosin light chain-2 [MLC2]) in cardiac muscle remain poorly understood. By integrating gene-targeted mouse and computational models, we have identified an indispensable role for ventricular Mlc2 (Mlc2v) phosphorylation in regulating cardiac muscle contraction. Cardiac myosin cycling kinetics, which directly control actin-myosin interactions, were directly affected, but surprisingly, Mlc2v phosphorylation also fed back to cooperatively influence calcium-dependent activation of the thin filament. Loss of these mechanisms produced early defects in the rate of cardiac muscle twitch relaxation and ventricular torsion. Strikingly, these defects preceded the left ventricular dysfunction of heart disease and failure in a mouse model with nonphosphorylatable Mlc2v. Thus, there is a direct and early role for Mlc2 phosphorylation in regulating actin-myosin interactions in striated muscle contraction, and dephosphorylation of Mlc2 or loss of these mechanisms can play a critical role in heart failure.     

Randomized controlled trial of a lay-facilitated angina management programme

furze g., cox h., morton v., chuang l.-h., lewin r.j.p., nelson p., carty r., norris h., patel n. & elton p. (2012)?Randomized controlled trial of a lay-facilitated angina management programme. Journal of Advanced Nursing68(10), 2267-2279. ABSTRACT: Aims. This article reports a randomized controlled trial of lay-facilitated angina management (registered trial acronym: LAMP). Background. Previously, a nurse-facilitated angina programme was shown to reduce angina while increasing physical activity, however most people with angina do not receive a cardiac rehabilitation or self-management programme. Lay people are increasingly being trained to facilitate self-management programmes. Design. A randomized controlled trial comparing a lay-facilitated angina management programme with routine care from an angina nurse specialist. Methods. Participants with new stable angina were randomized to the angina management programme (intervention: 70 participants) or advice from an angina nurse specialist (control: 72 participants). Primary outcome was angina frequency at 6?months; secondary outcomes at 3 and 6?months included: risk factors, physical functioning, anxiety, depression, angina misconceptions and cost utility. Follow-up was complete in March 2009. Analysis was by intention-to-treat; blind to group allocation. Results. There was no important difference in angina frequency at 6?months. Secondary outcomes, assessed by either linear or logistic regression models, demonstrated important differences favouring the intervention group, at 3?months for: Anxiety, angina misconceptions and for exercise report; and at 6?months for: Anxiety; Depression; and angina misconceptions. The intervention was considered cost-effective. Conclusion. The angina management programme produced some superior benefits when compared to advice from a specialist nurse.     

Carboxylesterase expression in human dental pulp cells: role in regulation of BisGMA-induced prostanoid production and cytotoxicity

Biocompatibility of dentin bonding agents (DBA) and composite resin may affect the treatment outcome (e.g., healthy pulp, pulpal inflammation, pulp necrosis) after operative restoration. Bisphenol-glycidyl methacrylate (BisGMA) is one of the major monomers present in DBA and resin. Prior studies focused on salivary esterase for metabolism and degradation of resin monomers clinically. This study found that human dental pulp cells expressed mainly carboxylesterase-2 (CES2) and smaller amounts of CES1A1 and CES3 isoforms. Exposure to BisGMA stimulated CES isoforms expression of pulp cells, and this event was inhibited by catalase. Exogenous addition of porcine esterase prevented BisGMA- and DBA-induced cytotoxicity. Interestingly, inhibition of CES by bis(p-nitrophenyl) phosphate (BNPP) and CES2 by loperamide enhanced the cytotoxicity of BisGMA and DBA. Addition of porcine esterase or N-acetyl-l-cysteine prevented BisGMA-induced prostaglandin E(2) (PGE(2)) and PGF(2α) production. In contrast, addition of BNPP and loperamide, but not mevastatin, enhanced BisGMA-induced PGE(2) and PGF(2α) production in dental pulp cells. These results suggest that BisGMA may induce the cytotoxicity and prostanoid production of pulp cells, leading to pulpal inflammation or necrosis via reactive oxygen species production. Expression of CES, especially CES2, in dental pulp cells can be an adaptive response to protect dental pulp against BisGMA-induced cytotoxicity and prostanoid release. Resin monomers are the main toxic components in DBA, and the ester group is crucial for monomer toxicity.     

Androgen Receptor Influences on Body Defense System via Modulation of Innate and Adaptive Immune Systems: Lessons from Conditional AR Knockout Mice

Upon insult, such as infection or tissue injury, the innate and adaptive immune systems initiate a series of responses to defend the body. Recent studies from immune cell-specific androgen receptor (AR) knockout mice demonstrated that androgen and its receptor (androgen/AR) play significant roles in both immune regulations. In the innate immunity, androgen/AR is required for generation and proper function of neutrophils; androgen/AR also regulates wound healing processes through macrophage recruitment and proinflammatory cytokine production. In adaptive immunity, androgen/AR exerts suppressive effects on development and activation of T and B cells. Removal of such suppression causes thymic enlargement and excessive export of immature B cells. Altogether, androgen/AR plays distinct roles in individual immune cells, and targeting androgen/AR may help in treatment and management of immune-related diseases.The immune system includes both innate and adaptive immune responses. Once insult to the body (eg, infection) is initially encountered, the innate system acts within minutes, followed some hours later by early induced responses conducted by recruited effector cells, such as neutrophils and macrophages, in a nonspecific manner.^1,2 In most cases, infections are eliminated by the innate immune system. When pathogens breach the first line of immune defense, however, the adaptive immune system is activated with antigen-specific effectors (eg, T and B cells), and the generation of memory cells ensures a long-lasting and prompt response to recurrent infection with the same pathogens. On the other hand, the context of the activated innate immunity also shapes the outcome of adaptive immune responses.³Androgen and androgen receptor (AR) signals control the development and function of both male and female reproductive systems.^4–6 The AR gene is located on the X chromosome in both the human and the murine genome. AR is a prototypical nuclear receptor, containing an N-terminal domain, a ligand-binding domain, a DNA-binding domain, and a C-terminal domain.⁷ After binding of its ligands, testosterone or 5α-dihydrotestosterone, AR translocates into the nucleus and binds to androgen responsive elements on the promoters or enhancers of target genes, thereby turning on their expression.⁸ The expression of AR has been detected in various immune cell lineages, including neutrophils, mast cells, macrophages, B cells, and T cells,^9–11 implying the involvement of androgen and its receptor (androgen/AR) in regulating the development and function of the immune system.It has long been suspected that, in both animals and humans, the male sex hormones may modulate the development and function of the immune system. Males are at higher risk of developing sepsis, acute respiratory distress, and multiorgan failure after soft-tissue traumatic hemorrhagic shock and thermal injury, in part because of immune suppression and abnormal activation of neutrophils.¹² On the other hand, males are less prone to autoimmune diseases. Of more than 70 chronic disorders categorized as autoimmune diseases, many affect predominantly women.^13,14 Various studies have uncovered important immune regulatory functions of androgen/AR (as discussed below), and such nonclassical roles of androgen/AR outside the reproductive system are important for understanding the pathogenesis of these immunological conditions.Recent studies using conditional AR knockout (ARKO) mice, with knockout of AR in selective immune cells, opened a new era for investigating the nonclassical roles of androgen/AR involved in immune regulation; these studies also suggest potential for the development of new therapeutic strategies for treating immune-related diseases.^6,15 In this review, we summarize the roles of androgen/AR in both the innate and adaptive components of the immune system (specifically neutrophils, macrophages, T cells, and B cells), as well as new evidence from studies using conditional ARKO mice. We also address the potential influences of androgen/AR on immune-related diseases.