Successful treatment of Candida parapsilosis and Pseudomonas aeruginosa infection using medical and surgical management in an injecting drug user with mitral and aortic valve endocarditis: a case report

<p>Abstract</p> <p>Introduction</p> <p>Polymicrobial endocarditis is a well-recognized problem in intravenous drug users and it accounts for 1 to 3% of endocarditis cases overall and up to 9% in other series. The most common combinations of organisms include <it>Staphylococcus aureus</it> and <it>Streptococcus pneumoniae</it> followed by <it>Staphylococcus aureus</it> and <it>Pseudomonas aeruginosa</it>. <it>Candida parapsilosis</it> endocarditis carries a mortality rate of 45%, and each infection with <it>Candida</it> or <it>Pseudomonas</it> endocarditis per se carries a very high mortality rate approaching 85% and 80%, respectively. The combination of <it>P. aeruginosa</it> and <it>C. parapsilosis</it> has never been encountered and there have been no earlier reports of the combination of <it>C. parapsilosis</it> and <it>P. aeruginosa</it> in adult intravenous drug users as a cause of endocarditis.</p> <p>Case presentation</p> <p>We present a 49-year-old man with bivalvular endocarditis with <it>P. aeruginosa</it> and <it>C. parapsilosis</it>. He had a prior bivalvular replacement in 2005 that became infected with the above microorganisms and he was treated with intravenous antibiotics. Because of ongoing intravenous drug use, a second valve replacement was denied. A few days later, the patient presented with septic shock secondary to <it>P. aeruginosa</it> and <it>C. parapsilosis</it> recurrent endocarditis. The infection was cured with a second bivalvular replacement and extended therapy with antibiotics and antifungals.</p> <p>Conclusion</p> <p>This is the first time a patient has presented with <it>P. aeruginosa</it> and <it>C. parapsilosis endocarditis</it>. Relapsing polymicrobial endocarditis can be cured with medical and surgical therapy.</p

Massive rearrangements of cellular MicroRNA signatures are key drivers of hepatocyte dedifferentiation

Hepatocytes are dynamic cells that, upon injury, can alternate between nondividing differentiated and dedifferentiated proliferating states in vivo . However, in two‐dimensional cultures, primary human hepatocytes (PHHs) rapidly dedifferentiate, resulting in loss of hepatic functions that significantly limits their usefulness as an in vitro model of liver biology, liver diseases, as well as drug metabolism and toxicity. Thus, understanding the underlying mechanisms and stalling of the dedifferentiation process would be highly beneficial to establish more‐accurate and relevant long‐term in vitro hepatocyte models. Here, we present comprehensive analyses of whole proteome and transcriptome dynamics during the initiation of dedifferentiation during the first 24 hours of culture. We report that early major rearrangements of the noncoding transcriptome, hallmarked by increased expression of small nucleolar RNAs, long noncoding RNAs, microRNAs (miRNAs), and ribosomal genes, precede most changes in coding genes during dedifferentiation of PHHs, and we speculated that these modulations could drive the hepatic dedifferentiation process. To functionally test this hypothesis, we globally inhibited the miRNA machinery using two established chemically distinct compounds, acriflavine and poly‐l ‐lysine. These inhibition experiments resulted in a significantly impaired miRNA response and, most important, in a pronounced reduction in the down‐regulation of hepatic genes with importance for liver function. Thus, we provide strong evidence for the importance of noncoding RNAs, in particular, miRNAs, in hepatic dedifferentiation, which can aid the development of more‐efficient differentiation protocols for stem‐cell‐derived hepatocytes and broaden our understanding of the dynamic properties of hepatocytes with respect to liver regeneration. Conclusion: miRNAs are important drivers of hepatic dedifferentiation, and our results provide valuable information regarding the mechanisms behind liver regeneration and possibilities to inhibit dedifferentiation in vitro

Lower age at menarche affects survival in older Australian women: results from the Australian Longitudinal Study of Ageing

Extent: 10p.Background: While menarche indicates the beginning of a woman's reproductive life, relatively little is known about the association between age at menarche and subsequent morbidity and mortality. We aimed to examine the effect of lower age at menarche on all-cause mortality in older Australian women over 15 years of follow-up. Methods: Data were drawn from the Australian Longitudinal Study of Ageing (n = 1,031 women aged 65-103 years). We estimated the hazard ratio (HR) associated with lower age at menarche using Cox proportional hazards models, and adjusted for a broad range of reproductive, demographic, health and lifestyle covariates. Results: During the follow-up period, 673 women (65%) died (average 7.3 years (SD 4.1) of follow-up for decedents). Women with menses onset < 12 years of age (10.7%; n = 106) had an increased hazard of death over the follow-up period (adjusted HR 1.28; 95%CI 0.99-1.65) compared with women who began menstruating aged ≥ 12 years (89.3%; n = 883). However, when age at menarche was considered as a continuous variable, the adjusted HRs associated with the linear and quadratic terms for age at menarche were not statistically significant at a 5% level of significance (linear HR 0.76; 95%CI 0.56 - 1.04; quadratic HR 1.01; 95%CI 1.00-1.02). Conclusion: Women with lower age at menarche may have reduced survival into old age. These results lend support to the known associations between earlier menarche and risk of metabolic disease in early adulthood. Strategies to minimise earlier menarche, such as promoting healthy weights and minimising family dysfunction during childhood, may also have positive longer-term effects on survival in later life.Lynne C Giles, Gary FV Glonek, Vivienne M Moore, Michael J Davies and Mary A Luszc

SUSY parameter determination at the LHC using cross sections and kinematic edges

We study the determination of supersymmetric parameters at the LHC from a global fit including cross sections and edges of kinematic distributions. For illustration, we focus on a minimal supergravity scenario and discuss how well it can be constrained at the LHC operating at 7 and 14 TeV collision energy, respectively. We find that the inclusion of cross sections greatly improves the accuracy of the SUSY parameter determination, and allows to reliably extract model parameters even in the initial phase of LHC data taking with 7 TeV collision energy and 1/fb integrated luminosity. Moreover, cross section information may be essential to study more general scenarios, such as those with non-universal gaugino masses, and distinguish them from minimal, universal, models.Comment: 22 pages, 8 figure

Expression and Differential Responsiveness of Central Nervous System Glial Cell Populations to the Acute Phase Protein Serum Amyloid A

Acute-phase response is a systemic reaction to environmental/inflammatory insults and involves hepatic production of acute-phase proteins, including serum amyloid A (SAA). Extrahepatically, SAA immunoreactivity is found in axonal myelin sheaths of cortex in Alzheimer's disease and multiple sclerosis (MS), although its cellular origin is unclear. We examined the responses of cultured rat cortical astrocytes, microglia and oligodendrocyte precursor cells (OPCs) to master pro-inflammatory cytokine tumour necrosis factor (TNF)-\u3b1 and lipopolysaccaride (LPS). TNF-\u3b1 time-dependently increased Saa1 (but not Saa3) mRNA expression in purified microglia, enriched astrocytes, and OPCs (as did LPS for microglia and astrocytes). Astrocytes depleted of microglia were markedly less responsive to TNF-\u3b1 and LPS, even after re-addition of microglia. Microglia and enriched astrocytes showed complementary Saa1 expression profiles following TNF-\u3b1 or LPS challenge, being higher in microglia with TNF-\u3b1 and higher in astrocytes with LPS. Recombinant human apo-SAA stimulated production of both inflammatory mediators and its own mRNA in microglia and enriched, but not microglia-depleted astrocytes. Co-ultramicronized palmitoylethanolamide/luteolin, an established anti-inflammatory/neuroprotective agent, reduced Saa1 expression in OPCs subjected to TNF-\u3b1 treatment. These last data, together with past findings suggest that co-ultramicronized palmitoylethanolamide/luteolin may be a novel approach in the treatment of inflammatory demyelinating disorders like MS

A formally verified compiler back-end

This article describes the development and formal verification (proof of semantic preservation) of a compiler back-end from Cminor (a simple imperative intermediate language) to PowerPC assembly code, using the Coq proof assistant both for programming the compiler and for proving its correctness. Such a verified compiler is useful in the context of formal methods applied to the certification of critical software: the verification of the compiler guarantees that the safety properties proved on the source code hold for the executable compiled code as well

What traits are carried on mobile genetic elements, and why?

Although similar to any other organism, prokaryotes can transfer genes vertically from mother cell to daughter cell, they can also exchange certain genes horizontally. Genes can move within and between genomes at fast rates because of mobile genetic elements (MGEs). Although mobile elements are fundamentally self-interested entities, and thus replicate for their own gain, they frequently carry genes beneficial for their hosts and/or the neighbours of their hosts. Many genes that are carried by mobile elements code for traits that are expressed outside of the cell. Such traits are involved in bacterial sociality, such as the production of public goods, which benefit a cell's neighbours, or the production of bacteriocins, which harm a cell's neighbours. In this study we review the patterns that are emerging in the types of genes carried by mobile elements, and discuss the evolutionary and ecological conditions under which mobile elements evolve to carry their peculiar mix of parasitic, beneficial and cooperative genes

Effects of experiment start time and duration on measurement of standard physicological variables

Duration and start time of respirometry experiments have significant effects on the measurement of basal values for several commonly measured physiological variables (metabolic rate, evaporative water loss and body temperature). A longer measurement duration reduced values for all variables for all start times, and this was an effect of reduced animal activity rather than random sampling. However, there was also an effect of circadian rhythm on the timing of minimal physiological values. Experiment start time had a significant effect on time taken to reach minimal values for all variables, ranging from 4:00 h ± 38 min (body temperature, start time 23:00 h) to 8:54 h ± 52 min (evaporative water loss, start time 17:00 h). It also influenced the time of day that minimal values were obtained, ranging from 22:24 h ± 40 min (carbon dioxide production, start time 15:00 h) to 06:00 h ± 57 min (oxygen consumption, start time 23:00 h), and the minimum values measured. Consequently both measurement duration and experiment start time should be considered in experimental design to account for both a handling and a circadian effect on the animal’s physiology. We suggest that experiments to measure standard physiological variables for small diurnal birds should commence between 17:00 h and 21:00 h, and measurement duration should be at least 9 h

RECO level \sqrt{s}_{min} and subsystem \sqrt{s}_{min}: improved global inclusive variables for measuring the new physics mass scale in missing energy events at hadron colliders

The variable \sqrt{s}_{min} was originally proposed in arXiv:0812.1042 as a model-independent, global and fully inclusive measure of the new physics mass scale in missing energy events at hadron colliders. In the original incarnation of \sqrt{s}_{min}, however, the connection to the new physics mass scale was blurred by the effects of the underlying event, most notably initial state radiation and multiple parton interactions. In this paper we advertize two improved variants of the \sqrt{s}_{min} variable, which overcome this problem. First we show that by evaluating the \sqrt{s}_{min} variable at the RECO level, in terms of the reconstructed objects in the event, the effects from the underlying event are significantly diminished and the nice correlation between the peak in the \sqrt{s}_{min}^{(reco)} distribution and the new physics mass scale is restored. Secondly, the underlying event problem can be avoided altogether when the \sqrt{s}_{min} concept is applied to a subsystem of the event which does not involve any QCD jets. We supply an analytic formula for the resulting subsystem \sqrt{s}_{min}^{(sub)} variable and show that its peak exhibits the usual correlation with the mass scale of the particles produced in the subsystem. Finally, we contrast \sqrt{s}_{min} to other popular inclusive variables such as H_T, M_{Tgen} and M_{TTgen}. We illustrate our discussion with several examples from supersymmetry, and with dilepton events from top quark pair production.Comment: 41 pages, 26 figure

Angiopoietin-1 inhibits tumour growth and ascites formation in a murine model of peritoneal carcinomatosis

Angiopoietin-1 is an important regulator of endothelial cell survival. Angiopoietin-1 also reduces vascular permeability mediated by vascular endothelial growth factor. The effects of angiopoietin-1 on tumour growth and angiogenesis are controversial. We hypothesised that angiopoietin-1 would decrease tumour growth and ascites formation in peritoneal carcinomatosis. Human colon cancer cells (KM12L4) were transfected with vector (pcDNA) alone (control) or vector containing angiopoietin-1 and injected into the peritoneal cavities of mice. After 30 days, the following parameters were measured: number of peritoneal nodules, ascites volume, and diameter of the largest tumour. Effects of angiopoietin-1 on vascular permeability were investigated using an intradermal Miles assay with conditioned media from transfected cells. Seven of the nine mice in the pcDNA group developed ascites (1.3±0.5 ml (mean±s.e.m.)), whereas no ascites was detectable in the angiopoietin-1 group (0 out of 10) (P<0.01). Number of peritoneal metastases (P<0.05), tumour volume, (P<0.05), vessel counts (P<0.01), and tumour cell proliferation (P<0.01) were significantly reduced in angiopoietin-1-expressing tumours. Conditioned medium from angiopoietin-1-transfected cells decreased vascular permeability more than did conditioned medium from control cells (P<0.05). Our results suggest that angiopoietin-1 is an important mediator of angiogenesis and vascular permeability and thus could theoretically serve as an anti-neoplastic agent for patients with carcinomatosis from colorectal cancer