Epidemiology of Candida albicans infections and role of non-Candida-albicans yeasts.
ABSTRACT Infections of the skin and the mucous membranes due to Candida species may occur either in immuncompromised or in non-immuncompromised patients. This is in contrast to systemic candidiasis (e.g. candidemia) which is only seen in severely immunocompromised patients. Bloodstream infections caused by Candida species are increasingly recognized in critical ill adult and pediatric individuals, with significant associated morbidity and mortality. Candida albicans is the single most common fungal species causing nosocomial infections. However, non-Candida albicans spp., including fluconazole-less-susceptible Candida glabrata, have become more common pathogens. In some patient populations such as hematological (neutropenic) patients Non-C. albicans species are detected much more frequently as compared to non-neutropenic patients in the intensive care. Non-C. albicans species are more likely to occur in patients, who receive or have received antifungal therapy with azoles (e.g. fluconazole). In this review the current epidemiological trends in mucosal and invasive candidiasis are discussed with regard to the role of non-Candida albicans species as the causative agent in immunocompromised patients.
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ABSTRACT: Sirtuins are a family of seven proteins in humans (SIRT1-SIRT7) that are involved in multiple cellular processes relevant to dermatology. The role of sirtuins in other organ systems is established. However, the importance of these proteins in dermatology is less defined. Recently, sirtuins gained international attention because of their role as "longevity proteins" that may extend and enhance human life. Sirtuins function in the cell via histone deacetylase and/or adenosine diphosphate ribosyltransferase enzymatic activity that target histone and non-histone substrates, including transcription regulators, tumor suppressors, structural proteins, DNA repair proteins, cell signaling proteins, transport proteins, and enzymes. Sirtuins are involved in cellular pathways related to skin structure and function, including aging, ultraviolet-induced photoaging, inflammation, epigenetics, cancer, and a variety of cellular functions including cell cycle, DNA repair and proliferation. This review highlights sirtuin-related cellular pathways, therapeutics and pharmacological targets in atopic dermatitis, bullous dermatoses, collagen vascular disorders, psoriasis, systemic lupus erythematosus, hypertrophic and keloid scars, cutaneous infections, and non-melanoma and melanoma skin cancer. Also discussed is the role of sirtuins in the following genodermatoses: ataxia telangiectasia, Cowden's syndrome, dyskeratosis congenita, Rubenstein-Taybi, Werner syndrome, and xeroderma pigmentosum. The pathophysiology of these inherited diseases is not well understood, and sirtuin-related processes represent potential therapeutic targets for diseases lacking suitable alternative treatments. The goal of this review is to bring attention to the dermatology community, physicians, and scientists, the importance of sirtuins in dermatology and provide a foundation and impetus for future discussion, research and pharmacologic discovery.Archives for Dermatological Research 02/2013; · 2.71 Impact Factor
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ABSTRACT: Microorganisms use two-component signal transduction (TCST) systems to regulate the response of the organism to changes of environmental conditions. Such systems are absent from mammalian cells and are thus of interest as drug targets. Fungal TCST systems are usually composed of a hybrid histidine kinase, comprising the histidine kinase (HisKA) domain and a receiver domain, a histidine phosphotransfer protein and a response regulator. Among the 11 groups of fungal histidine kinases, group III histidine kinases are of particular relevance as they are essential for the activity of different groups of fungicides. A characteristic feature is the N-terminal amino acid repeat domain comprising multiple HAMP domains, of which the function is still largely unknown. In Candida albicans, a fungal human pathogen, three histidine kinases were identified, of which CaNik1p is a group III histidine kinase. Heterologous expression of this protein in Sacchromyces cerevisiae conferred susceptibility to different fungicides. Fungicide activity was associated with phosphorylation of the mitogen activated protein kinase Hog1p. We have constructed mutated versions of CaNik1p, from which either all HAMP domains were deleted (CaNik1pDeltaHAMP) or in which the histidine kinase or the receiver domains were not-functional. Expression of CaNIK1DeltaHAMP in S. cerevisiae led to severe growth inhibition. Normal growth could be restored by either replacing the phosphate-accepting histidine residue in CaNik1pDeltaHAMP or by expressing CaNIK1DeltaHAMP in S. cerevisiae mutants, in which single genes encoding several components of the HOG pathway were deleted. Expression of proteins with non-functional histidine kinase or receiver domains resulted in complete loss of susceptibility to antifungals, such as fludioxonil. Conditions leading to growth inhibition of transformants also led to phosphorylation of the MAP kinase Hog1p. Our results show that functional histidine kinase and receiver domains of CaNik1p were essential for antifungal susceptibility and for activation of the Hog1p. Moreover, for the first time we show that deletion of all HAMP domains from CaNik1p led to activation of Hog1p without an external stimulus. This phenotype was similar to the effects obtained upon treatment with fungicides, as in both cases growth inhibition correlated with Hog1p activation and was dependent on the functionality of the conserved phosphate-accepting histidine residue.BMC Microbiology 09/2013; 13(1):209. · 3.10 Impact Factor
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ABSTRACT: BACKGROUND: Whether intestinal dysmotility and the use of a proton pump inhibitor (PPI) either independently or together contributes to small intestinal bacterial overgrowth (SIBO), and/or small intestinal fungal overgrowth (SIFO) is not known. AIM: To investigate the role of dysmotility and PPI use in patients with persistent gastrointestinal complaints. METHODS: Patients with unexplained gastrointestinal symptoms and negative endoscopy/radiology tests completed a validated symptom questionnaire and underwent 24-h ambulatory antro-duodeno-jejunal manometry (ADJM). Simultaneously, duodenal aspirate was obtained for aerobic, anaerobic and fungal culture. Dysmotility was diagnosed by (>2): absent phase III MMC, absent/diminished postprandial response, diminished amplitude of antral/intestinal phasic activity, impaired antro-duodenal coordination. Bacterial growth ≥10(3) CFU/mL or fungal growth was considered evidence for SIBO/SIFO. PPI use was documented. Correlation of symptoms with presence of SIBO or SIFO was assessed. RESULTS: One hundred and fifty subjects (M/F = 47/103) were evaluated; 94/150 (63%) had overgrowth: 38/94 (40%) had SIBO, 24/94 (26%) had SIFO and 32/94 (34%) had mixed SIBO/SIFO. SIBO was predominately due to Streptococcus, Enterococcus, Klebsiella and E. coli. SIFO was due to Candida. Eighty of 150 (53%) patients had dysmotility and 65/150 (43%) used PPI. PPI use (P = 0.0063) and dysmotility (P = 0.0003) were independent significant risk factors (P < 0.05) for overgrowth, but together did not pose additional risk. Symptom profiles were similar between those with or without SIBO/SIFO. CONCLUSIONS: Dysmotility and PPI use were independent risk factors for SIBO or SIFO and were present in over 50% of subjects with unexplained gastrointestinal symptoms. Diagnosis of overgrowth requires testing because symptoms were poor predictors of overgrowth.Alimentary Pharmacology & Therapeutics 04/2013; · 4.55 Impact Factor