Emerging Pathogens of the Candida Species

In recent years, opportunistic and nosocomial fungal pathogens have been dominated by yeasts of the genus Candida. Most of the research has focused on Candida albicans since it is the most prominent etiological agent. There are numerous publications that describe the biology, virulence factors, morphology, immunity, genomics, diseases, and laboratory aspects of Candida albicans. In this chapter we offer a historic perspective of C. albicans and focus on other non-albicans candida (NAC) that cause serious disease. We review the current knowledge of emerging NAC pathogens with useful graphics and current references. This chapter is laid out as an overview and is geared for students seeking basic information and may be superficial for an infectious diseases clinician

Bishop score and transvaginal ultrasound for preinduction cervical assessment: a randomized clinical trial

Background: The objective was to compare transvaginal ultrasound with the Bishop score for preinduction cervical assessment and for choice of induction agent. Methods: 150 women were randomized to have preinduction cervical assessment for choice of induction agent based on either Bishop score or transvaginal ultrasound. The primary outcome measure was the percentage of women who were administered prostaglandin as a preinduction agent. The criteria for considering the cervix as unripe and thus for using prostaglandin were either a Bishop score <6 or cervical wedging of <30% of the total cervical length. Secondary outcome measures included interval to active phase, interval to delivery and rate of Caesarean section and fetal outcome. Results: While 85% of women received prostaglandin in the Bishop score group, only 53% of them did in the transvaginal ultrasound group (p =0.001). The interval to active phase, interval to delivery, rate of Caesarean section for failed induction and fetal outcomes were similar in both groups.Conclusions: With the suggested cut-off values of a Bishop score <6 and wedging <30%, the use of transvaginal ultrasound instead of Bishop score for preinduction cervical assessment to choose induction agent significantly reduces the need for intracervical prostaglandin treatment without adversely affecting the success of induction

Green Marketing: The Challenges Ahead

Environmental responsibility has been added to the corporate agenda in the 21st century. Both the government and society hold businesses accountable to operate in an environmentally friendly manner. And in order to survive in this changing environment business firms have started adopting and embracing ‘green’ marketing practices to conform to green pressures and environmental legislation. Green marketing refers to all practices that concentrate on maintaining an ecological balance while fulfilling the motive of wealth maximization for a business organization. It is a holistic marketing concept wherein the production, marketing consumption and disposal of products is done in a manner that is less detrimental to the environment. With growing awareness about the implications of global warming, non-biodegradable solid waste, harmful impact of pollutants etc. business organizations also feel obliged to contribute towards creating and functioning in an environmental friendly atmosphere. The objective of this paper is to discuss the concept of green marketing and challenges in the way of green marketing with some suggestions to overcome these challenges.

Novel paths to antifungal therapeutics

Adhesion to medical device and host cell surfaces are crucial steps during pathogenesis by fungi such as Candida albicans, which is especially dangerous to immunocompromised individuals such as AIDS patients. We have identified a small molecule that inhibits adhesion of C. albicans to polystyrene and to cultured human epithelial cells. Moreover, this compound is able to coat plastic surfaces and make them resistant to colonization by fungal biofilms. Therefore, this compound has the potential to be widely useful as a novel therapeutic and/or as a coating on medical devices. Rationale: C. albicans is the most widespread fungal pathogen of humans and one of the most frequent hospital-acquired infections. The estimated annual cost of treating nosocomial Candida infections exceeds $1 billion per year. As an opportunistic pathogen, it is responsible for common clinical problems including oral thrush and vaginitis, but can also lead to life-threatening systemic infections (candidiasis) in immunocompromised individuals, resulting in 30-50% mortality rates. Contributing to these problems is the ability of C. albicans to develop resistance to antifungal drugs. Moreover, most effective antifungal drugs also cause serious side effects, in many cases because of the significant homology between mammalian and fungal drug targets. Therefore, new antifungal drugs are a high medical priority. Surface adhesion, morphological switching, and biofilm formation are interrelated factors that contribute directly to C. albicans virulence. Therefore, compounds that impair these processes would have promising properties as first step towards new antifungal therapeutics. Preliminary Studies: Efficient adhesion is required for formation of aggressive biofilms, which in turn make Candida a successful pathogen. Therefore, we identified compounds that prevent adhesion of Candida albicans to polystyrene surfaces. Because the assays in this proposal are based on altering the behavior of intact cells, we avoid the complication of compounds unable to cross the cell wall and membranes. Our initial search for adhesion inhibitors was conceptually simple, based on dye binding to monitor yeast adhesion to surfaces. We identified 41 compounds that reduced adhesion to Candidastrain confirmed that most of the reordered compounds indeed inhibit adhesion to polystyrene (Figure 1). Figure 1. Compound #4 inhibits C. albicans adhesion to polystyrene. GFP-expressing wild type or non-adherent edt1 mutant C. albicans cells were plated into 96 well plates with DMSO or 25 mM compound 4 as indicated. Plates were incubated for 4 hours at 37oC. Media was then decanted and plates were washed 3 times prior to fluorescence microscopy. Human cell adhesion: To determine whether any candidate compounds would affect interactions with biological targets as well as inert surfaces, we also tested how the candidate compounds affect C. albicans adherence to human cells, using monolayers of human lung epithelial cells. The GFP-encoding cells allowed us to use both microscopy and fluorescence measurements to detect fungal cells that remained bound after washing. We observed that “compound #4”, but not other candidate compounds, reduced the interaction of C. albicans with the human cells to background levels. We also verified that compound 4 did not affect the viability of this human cell line, even at concentrations much higher (250 mM) than those used in the adhesion assay (data not shown). Plastic coating: Compound 4 also inhibits Candida adhesion to polystyrene when it is incubated with the plastic prior to the addition of the cells. Therefore, compound 4 not only has effects on Candida cell morphology in the absence of surface adhesion, it also renders plastic surfaces resistant to subsequent Candida binding. Together, our data suggest that compound 4 may not only be effective at combating fungal infections, but could also have potential use as a compound to prevent multiple types of unwanted microbial colonization

The evolution of drug resistance in clinical isolates of Candida albicans

Candida albicans is both a member of the healthy human microbiome and a major pathogen in immunocompromised individuals. Infections are typically treated with azole inhibitors of ergosterol biosynthesis often leading to drug resistance. Studies in clinical isolates have implicated multiple mechanisms in resistance, but have focused on large-scale aberrations or candidate genes, and do not comprehensively chart the genetic basis of adaptation. Here, we leveraged next-generation sequencing to analyze 43 isolates from 11 oral candidiasis patients. We detected newly selected mutations, including single-nucleotide polymorphisms (SNPs), copy-number variations and loss-of-heterozygosity (LOH) events. LOH events were commonly associated with acquired resistance, and SNPs in 240 genes may be related to host adaptation. Conversely, most aneuploidies were transient and did not correlate with drug resistance. Our analysis also shows that isolates also varied in adherence, filamentation, and virulence. Our work reveals new molecular mechanisms underlying the evolution of drug resistance and host adaptation.National Science Foundation (U.S.). Graduate Research Fellowship ProgramHoward Hughes Medical InstituteHelen Hay Whitney Foundation (Postdoctoral Fellowship)Alfred P. Sloan FoundationNational Institutes of Health (U.S.) (Grant 8DP1CA174427)National Institutes of Health (U.S.) (Grant 2R01CA119176-01

Interleukin-10 Producing Regulatory B Cells Transformed CD4+CD25− Into Tregs and Enhanced Regulatory T Cells Function in Human Leprosy

Regulatory B cells (Bregs) are known to exhibit their regulatory functions through interleukin-10 (IL-10) cytokine which suppress inflammation. There are only a few studies explaining the phenotype and functioning of these cells in contribution to host immunity in leprosy. Here, we evaluated the role of IL-10 producing Bregs in the pathogenesis of leprosy and assessed their immunoregulatory effects on Tregs and effector T cells. We found an increased frequency of Bregs and increased expression of their immune modulatory molecules (IL-10, FoxP3, and PDL-1) in leprosy patients. The potential immunoregulatory mechanism of Bregs was also investigated using MACS sorted Teff (CD4+CD25−) and Treg (CD4+CD25+) cells were cocultured with Bregs to elucidate the effects of Bregs on effector T and regulatory T cells. Cell coculture results showed that purified Bregs cells from leprosy patients convert CD4+CD25− cells into CD4+CD25+ cells. Cell coculture experiments also demonstrated that leprosy derived IL-10 producing Bregs enhance FoxP3 and PD-1 expression in Tregs and enhanced Tregs activity. Blocking of IL-10 receptor confirmed that IL-10 producing Breg has immunomodulatory effect on Tregs and effector T cells as effector T cells are not converted into Tregs and enhanced expression of FoxP3 and PD-1 was not observed on Tregs. Collectively, these findings demonstrate that IL-10 producing Breg cells play an important mechanism in controlling the immunopathogenesis of leprosy and have an immunomodulatory effect on Tregs and effector T cells. Our findings may pave way for novel targets of IL-10 producing Bregs for immunotherapy in leprosy patients

Candida albicans Induces Selective Development of Macrophages and Monocyte Derived Dendritic Cells by a TLR2 Dependent Signalling

As TLRs are expressed by haematopoietic stem and progenitor cells (HSPCs), these receptors may play a role in haematopoiesis in response to pathogens during infection. We have previously demonstrated that in in vitro defined conditions inactivated yeasts and hyphae of Candida albicans induce HSPCs proliferation and differentiation towards the myeloid lineage by a TLR2/MyD88 dependent pathway. In this work, we showed that C. albicans invasive infection with a low virulence strain results in a rapid expansion of HSPCs (identified as LKS cells: Lin− c-Kit+ Sca-1+ IL-7Rα−), that reach the maximum at day 3 post-infection. This in vivo expansion of LKS cells in TLR2−/− mice was delayed until day 7 post- infection. Candidiasis was, as expected, accompanied by an increase in granulopoiesis and decreased lymphopoiesis in the bone marrow. These changes were more pronounced in TLR2−/− mice correlating with their higher fungal burden. Accordingly, emigration of Ly6Chigh monocytes and neutrophils to spleen was increased in TLR2−/− mice, although the increase in macrophages and inflammatory macrophages was completely dependent on TLR2. Similarly, we detected for the first time, in the spleen of C. albicans infected control mice, a newly generated population of dendritic cells that have the phenotype of monocyte derived dendritic cells (moDCs) that were not generated in TLR2−/− infected mice. In addition, C. albicans signalling through TLR2/MyD88 and Dectin-1 promotes in vitro the differentiation of Lin− cells towards moDCs that secrete TNF-α and are able to kill the microorganism. Therefore, our results indicate that during infection C. albicans can directly stimulate progenitor cells through TLR2 and Dectin-1 to generate newly formed inflammatory macrophages and moDCs that may fulfill an essential role in defense mechanisms against the pathogen

Markers of Dysglycaemia and Risk of Coronary Heart Disease in People without Diabetes: Reykjavik Prospective Study and Systematic Review

BACKGROUND: Associations between circulating markers of dysglycaemia and coronary heart disease (CHD) risk in people without diabetes have not been reliably characterised. We report new data from a prospective study and a systematic review to help quantify these associations. METHODS AND FINDINGS: Fasting and post-load glucose levels were measured in 18,569 participants in the population-based Reykjavik study, yielding 4,664 incident CHD outcomes during 23.5 y of mean follow-up. In people with no known history of diabetes at the baseline survey, the hazard ratio (HR) for CHD, adjusted for several conventional risk factors, was 2.37 (95% CI 1.79-3.14) in individuals with fasting glucose > or = 7.0 mmol/l compared to those or = 7 mmol/l at baseline were excluded, relative risks for CHD, adjusted for several conventional risk factors, were: 1.06 (1.00-1.12) per 1 mmol/l higher fasting glucose (23 cohorts, 10,808 cases, 255,171 participants); 1.05 (1.03-1.07) per 1 mmol/l higher post-load glucose (15 cohorts, 12,652 cases, 102,382 participants); and 1.20 (1.10-1.31) per 1% higher HbA(1c) (9 cohorts, 1639 cases, 49,099 participants). CONCLUSIONS: In the Reykjavik Study and a meta-analysis of other Western prospective studies, fasting and post-load glucose levels were modestly associated with CHD risk in people without diabetes. The meta-analysis suggested a somewhat stronger association between HbA(1c) levels and CHD risk

Kinome Profiling Reveals an Interaction Between Jasmonate, Salicylate and Light Control of Hyponastic Petiole Growth in Arabidopsis thaliana

Plants defend themselves against infection by biotic attackers by producing distinct phytohormones. Especially jasmonic acid (JA) and salicylic acid (SA) are well known defense-inducing hormones. Here, the effects of MeJA and SA on the Arabidopsis thaliana kinome were monitored using PepChip arrays containing kinase substrate peptides to analyze posttranslational interactions in MeJA and SA signaling pathways and to test if kinome profiling can provide leads to predict posttranslational events in plant signaling. MeJA and SA mediate differential phosphorylation of substrates for many kinase families. Also some plant specific substrates were differentially phosphorylated, including peptides derived from Phytochrome A, and Photosystem II D protein. This indicates that MeJA and SA mediate cross-talk between defense signaling and light responses. We tested the predicted effects of MeJA and SA using light-mediated upward leaf movement (differential petiole growth also called hyponastic growth). We found that MeJA, infestation by the JA-inducing insect herbivore Pieris rapae, and SA suppressed low light-induced hyponastic growth. MeJA and SA acted in a synergistic fashion via two (partially) divergent signaling routes. This work demonstrates that kinome profiling using PepChip arrays can be a valuable complementary ∼omics tool to give directions towards predicting behavior of organisms after a given stimulus and can be used to obtain leads for physiological relevant phenomena in planta

Nations within a nation: variations in epidemiological transition across the states of India, 1990–2016 in the Global Burden of Disease Study

18% of the world's population lives in India, and many states of India have populations similar to those of large countries. Action to effectively improve population health in India requires availability of reliable and comprehensive state-level estimates of disease burden and risk factors over time. Such comprehensive estimates have not been available so far for all major diseases and risk factors. Thus, we aimed to estimate the disease burden and risk factors in every state of India as part of the Global Burden of Disease (GBD) Study 2016