, 2008; Li et al., 2009, 2010; Cheung et al., 2011). USA300 strains exhibited enhanced production of dermonecrotic lesions in skin abscess models when compared to HA-MRSA clones (Li et al., 2009, 2010; Cheung et al., 2011), and USA300 was more lethal in a rat model of pneumonia compared with a USA400 isolate (Montgomery et al., 2008). Furthermore, USA300 strains were more lethal in septic infections compared with archaic and Iberian clones as well as ST239 clones (Brazilian clones) (Li et al., 2009). When compared with other CA-MRSA

clones, USA300 isolates generally exhibit increased virulence with the exception of ST80 and USA1000, which also possess enhanced virulence (Li et al., 2010). In contrast, nearly every clone of HA-MRSA tested was significantly less virulent than USA300 with the only exception being USA500 HA-MRSA (Li et al., 2009, 2010). This is Selleck AZD6738 of particular interest in that USA300 clones descended from USA500 via the acquisition of a prophage containing panton-valentine leukotoxin (PVL), a mobile arginine catabolic mobile element (ACME) and enterotoxins K and Q (see below) (Li et al., 2009). Thus, the source

of USA300 hypervirulence may have originally evolved in the HA-MRSA isolates belonging to USA500. However, for unknown reasons, despite exhibiting hypervirulence in animal infection models, USA500 clones remain relegated to healthcare settings and do not cause significant CA-MRSA disease. Whether CA-MRSA Cell Cycle inhibitor USA300 clones exhibit hypervirulence in human disease has been difficult to directly discern, however, recent population-based clinical data are beginning to corroborate conclusions drawn from laboratory animal model experiments. In humans, USA300 S. aureus primarily causes skin infections of which, it can account for up to 98% of all MRSA presenting as skin/soft tissue infections to US emergency rooms (Talan et al., 2011). In addition, USA300 can also cause more invasive disease such as bacteremia (Seybold et al., 2006), endocarditis (Haque

et al., 2007), and necrotizing fasciitis (Miller et al., 2005), a condition almost never associated with S. aureus. In particular, pulmonary 4-Aminobutyrate aminotransferase infections caused by USA300 S. aureus can lead to aggressive and often fatal necrotizing pneumonia (Francis et al., 2005; Hageman et al., 2006; Klevens et al., 2007). The populations most at risk for contracting USA300 CA-MRSA are military personnel (Ellis et al., 2009), athletes (Center for Disease Control & Prevention, 2003b, c, 2009b), prisoners (Center for Disease Control & Prevention, 2001, 2003a; Maree et al., 2010), African Americans (Klevens et al., 2007; Kempker et al., 2010), daycare attendees (Buckingham et al., 2004; Kaplan et al., 2005), and men who have sex with men (Sztramko et al., 2007). Patients contracting CA-MRSA are, on average, younger than those with HA-MRSA and otherwise generally healthy (Nair et al., 2011; Whitby et al., 2011). Furthermore, CA-MRSA is often associated with worse clinical outcomes.

We isolated splenic naive CD4 T cells from C57BL/6 mice and stimulated them in vitro in either Th1 or Selleck Fluorouracil Th2 polarizing conditions. Cells were cross-linked and sonicated, and the chromatin was immunoprecipitated with either an anti-GATA-3 or anti-MTA-2 antibody. GATA-3

bound to Th2 LCR (RHS4, RHS5, RHS6, and RHS7), the promoters of il4, il5 and il13 genes, and enhancers (CNS-1 and CNS-2/HSV) in a Th2-specific manner (Fig. 2). This result shows that GATA-3 binds to the Th2 cytokine locus globally and to Th2 specifically. The MTA-2 also bound to Th2 LCR (RHS4, RHS5, RHS6, and RHS7) and promoters of Th2 cytokine genes, and enhancers (CNS-1/HSS, CNS-2/HSV) (Fig. 2). However, in contrast to GATA-3, MTA-2 bound to these regions in a Th1-specific manner (Fig. 2). Therefore, the overall binding of MTA-2 and GATA-3 on the Th2 cytokine C59 wnt concentration locus was mutually exclusive (Fig. 2). Interestingly, both GATA-3 and MTA-2 bound to the promoter of the ifng gene in Th2 cells (Fig. 2). The simultaneous binding of GATA-3 and MTA-2 on the ifng promoter was confirmed by a double-chromatin immunoprecipitation experiment. Chromatin from Th1 or Th2 cells was first immunoprecipitated with an anti-GATA-3 antibody, and the bound antibody was detached from the chromatin by treating with DTT. The eluted chromatin was then immunoprecipitated with the anti-MTA-2 antibody. The result confirms that GATA-3 and MTA-2 bound to the ifng promoter simultaneously

in Th2 cells (Fig. 3). Next, we examined whether the binding of MTA-2 to ifng promoter is dependent on GATA-3. For this purpose, we used siRNA-mediated reduction (knockdown) of GATA-3 protein in EL4 cells. We transfected gata3 siRNA into EL4 cells and measured the protein level of GATA-3 by immunoblotting (Fig. 4a).

Treatment with gata3 siRNA led to a significant reduction of GATA-3 protein level in EL4 cells (Fig. 4a). The expression of ifng gene was increased by treatment with gata3 siRNA (Fig. 4b), consistent with the previous reports.13,14 Interestingly, the binding of MTA-2 to ifng promoter was abolished by gata3 siRNA (Fig. 4c). However, the binding of MTA-2 to myc promoter, which has been shown previously24,25 but has not been Non-specific serine/threonine protein kinase shown to have any relevance to GATA-3, was not affected by gata3 siRNA (Fig. 4c). These results strongly suggest that the binding of MTA-2 to ifng promoter is specifically dependent on GATA-3. We also examined whether MTA-2 affects the functional activity of GATA-3. The GATA-3 expression vector was transfected with reporter constructs that contain IL4P-luciferase (IL4P) or RHS7-IL4P-luciferase (IL4P-RHS7).9 Introduction of GATA-3 transactivated the transcription of the reporter gene about two-fold in IL4P and about three-fold in RHS7-IL4P constructs after treatment with PMA + ionomycin (Fig. 5). These results suggest that the il4 promoter and RHS7 are GATA-3 responsible elements, and are consistent with the ChIP data indicating that GATA-3 bound to these regions (Fig. 2).

11 Patients with a family history of diabetes, age > 45 years, ATSI and obesity are at an increased risk for the future development of diabetes and as such consideration for screening all high-risk patients with a 2 h OGTT rather than just two fasting plasma glucose measurements should be made.12 Databases searched: MeSH terms and text words for kidney transplantation were combined with MeSH terms and text

words for living donor and combined with MeSH terms and text words for glucose intolerance. find more The search was carried out in Medline (1950–July Week 3, 2008). The Cochrane Renal Group Trials Register was also searched for trials not indexed in Medline. Date of searches: 24 July 2008. There are no published studies that could be located that

quantify the risk to donors with impaired glucose tolerance prior to transplant nephrectomy. This likely reflects the common practice of avoiding these donors. Due to the lack of information on the outcome in living kidney donors with Selleckchem Regorafenib pre-donation impaired glucose tolerance we commenced our review by examining the incidence of type 2 diabetes mellitus in healthy living kidney donors (i.e. normal blood pressure, glomerular filtration rate > 80 mL/min and normal amount of proteinuria pre-donation). There are 11 studies that describe the development of diabetes mellitus following living kidney donation 3-mercaptopyruvate sulfurtransferase in donors.13–23 These studies describe an incidence of 1.5–7.4% with a follow

up of more than 20 years in some studies. All of the studies suffer with the following methodological problems: 1 cross-sectional – none were designed to follow donors prospectively from the time of transplant and most examine donors cross-sectionally post transplant, Fehrman-Ekholm et al. described 348 Swedish living kidney donors at a mean of 12 years post-donation. They represented 87% of the total living donors from Stockholm between 1964 and 1995 who were still alive. Despite normal OGTT for all donors at baseline, six developed type 2 diabetes mellitus.13 In another study, the authors were able to obtain information on 33% (256/773) of living kidney donors over 20 years post-donation. Of these, 19 developed type 2 diabetes mellitus, despite the 10 with a positive family history having negative baseline OGTT.14 It is unclear the effect donation has on the incidence of developing diabetes mellitus due to the lack of suitable controls. Diabetic nephropathy is currently the most common cause of end-stage kidney disease in developed countries. The risk of developing diabetic nephropathy varies between studies, with one study documenting a prevalence of 25.4% for microalbuminuria and <10% for macroalbuminuria or end-stage kidney disease in 27 805 type 1 diabetic patients.24 A similar prevalence was observed in type 2 diabetes.

[9] During the last few years, several studies have demonstrated that S100 proteins

can function as DAMP molecules.[10, 11] An increasing amount of evidence also indicates that members of this protein family, and in particular RG7420 cell line S100A8 and S100A9, may represent novel markers for inflammation and autoimmune diseases.[13-15] S100A9, a small protein with molecular weight 14 000, is constitutively expressed in neutrophils and monocytes.[18, 19] S100A9 has a central domain flanked by two EF-hand Ca2+ binding-motifs and interacts with S100A8 forming a complex called calprotectin,[12] the pro-inflammatory function of which has been well characterized.[16-20] In particular, calprotectin triggers NF-κB activation and cytokine secretion,[21-24] promotes chemotaxis of neutrophils at the site of inflammation,[25, BI 2536 research buy 26] induces apoptosis of numerous cell lines[27] and has anti-microbial activity.[28] Despite this progress, the possible pro-inflammatory effects of S100A9 itself remain elusive. In this work, we set out to investigate possible pro-inflammatory effects of human and mouse S100A9 on monocytes. More specifically, we have compared the activities of S100A9 and LPS to determine whether PAMP and DAMP molecules would induce distinct responses in target cells. The human monocytic leukaemia cell line THP-1 (purchased from American Type Culture Collection, Manassas, VA) was grown in RPMI-1640

culture medium (Invitrogen, Stockholm, Sweden) supplemented with 10% fetal

bovine serum (Invitrogen), 2 mm glutamine (Sigma-Aldrich, St Louis, MO), 1 mm sodium pyruvate, 10 mm HEPES, 100 U/ml penicillin and 100 μg/ml streptomycin (P/S; Invitrogen), at 37° in 5% CO2. All the experiments were performed with a cell density of 0·2 × 106 in 96-well plates or 1 × 106 in 24-well plates. Megestrol Acetate Bone-marrow-derived dendritic cells (BM-DC) were obtained from bone marrow cells of 15- to 20-week-old mice. Bone marrow cells were withdrawn from the femurs and tibias of the mice and cultured for 7 days in RPMI-1640 medium supplemented with 10% fetal bovine serum, 2 mm glutamine, 1 mm sodium pyruvate, 10 mm HEPES and 10% supernatant collected from granulocyte–macrophage colony-stimulating factor gene transfected J558L cell line. The purity of the BM-DC population was assessed by flow cytometry after CD11c labelling. Fifteen- to 20-week-old C57BL/6 wild-type and C57BL/6 TLR4 knockout (KO) mice (both bought from TACONIC, Hudson, NY) and C57BL/6 RAGE-KO mice (produced in the laboratory of J. Roth) were used for the experiments. The mice were kept in the animal facility at the Biomedical Centre at Lund University. The experiments were approved by the local ethics committee for use of animals in research. BL21 (DE3)/pET1120 Escherichia coli cells were treated with isopropyl-β-d-1-thiogalactopyranoside for some hours at 37° to induce h-S100A9 expression.

The severe and uncontrolled inflammatory reactions observed in the TGF-β1 knock-out mouse attests to the physiological role of TGF-β as an endogenous anti-inflammatory cytokine [42]. Even though in this study Gram-negative

E. coli stimulated substantial amount of proinflammatory cytokines, the induction of pro- and anti-inflammatory cytokines with live Gram-positive bacteria (including GIT simulated bacteria), on average, was significantly higher. Hessle et al. [13] reported that Gram-positive bacteria appeared to stimulate IL-12 production and Gram-negative bacteria stimulate IL-10 production preferentially. However, concordant with observations reported in Berg et al. [43] and in our study, Gram-negative E. coli induced the secretion selleck compound of significant concentrations of proinflammatory cytokines by PBMCs and the CRL-9850 cell line. While the mechanisms by which some bacteria induce the production

of IL-10 are unclear, LPS of Gram-negative bacteria may stimulate this anti-inflammatory response [43]. Compounds other than LPS in lactobacilli probably contributed to the ability of these probiotic bacteria to stimulate an anti-inflammatory cytokine response. Probiotic www.selleckchem.com/products/Metformin-hydrochloride(Glucophage).html LAVRI-A1, LGG, B94 and BL536 induced substantial amounts of pro-and anti-inflammatory cytokines in line with previous studies [44], with the balance skewed towards the anti-inflammatory response in our study. A demonstration of the utility of this response is the finding that LGG reduced inflammation in Crohn’s disease [45]. The human gut microbiota

has been estimated recently to consist of at least 400 different species [46], and it is likely that the potency of each of these species to influence immune homeostasis is different. Indeed, cytokine profiles in co-cultures of bacteria with PBMC show marked differences between strains [23]. In addition, the effects of lactobacilli supplementation on experimental autoimmune encephalomyelitis have been shown to be highly strain-dependent [47]. It is therefore conceivable that the contradicting results Pyruvate dehydrogenase lipoamide kinase isozyme 1 found in the human trials can be explained partly by differences in the immunomodulatory capacity of the strains used. The fact that the killed bacteria in our study were inefficient in inducing substantial amounts of pro- and anti-inflammatory cytokines compared to live bacteria suggests that extra- and intracellular bacterial components as well as metabolites probably contribute to cytokine production [48]. Conceivably, a combination of certain bacterial fragments, metabolites produced in situ and particular structural motifs may need to interact with receptors on monocytes to induce optimal cytokine synthesis [21,49]. Cross et al. [50] and Macpherson and Harris [51] reported that live lactobacilli were more potent inducers of cytokine production in mammalian leucocytes compared to killed bacteria, similar to our findings.

Hayakawa and Smyth reported a stronger cytotoxicity in CD27− NK cells compared with CD27+ NK cells, which are in part CXCR3+23. However, only purified CD11b+ NK cells were used in the cytotoxicity assays they performed. CD11b has been associated with elevated levels of cytolytic function of mature NK cells. Whereas all CXCR3− NK cells were CD11b+ and highly cytolytic, a fraction of CXCR3+ NK cells lacked CD11b expression. CXCR3+ NK cells displayed lower cytotoxicity, and this could be due to their different developmental stage. Interestingly, the proliferative response of CXCR3+ NK cells to IL-21 was far greater than that of CXCR3− NK cells. Although inhibition of proliferation of

mouse NK cells by IL-21 has been reported, the effect was not analyzed for different NK-cell subsets 45. For human Selleckchem Panobinostat NK cells we showed that CD56bright NK cells exhibited a strong proliferative response towards IL-21 when combined with IL-2, although IL-21R is equally expressed on CD56dim and Kinase Inhibitor Library cell assay CD56bright NK cells 31. These results also correspond

to our murine data. Compared with CXCR3− NK cells, slightly higher percentages of CXCR3+ NK cells displayed IL-21R expression (data not shown). As shown for the human system, a specific role for STAT proteins can be suggested for the induction of proliferation of murine NK cells by IL-21 and IL-2. The two cytokines may induce the formation of particular STAT protein dimers, which could differentially affect the proliferation of CXCR3− and CXCR3+ NK cells. The combination and properties of STAT complexes still have to be determined in detail. In addition, signaling via IL-21R requires receptor heterodimerization with the γ chain (CD132), which is also shared by IL-2R and IL-15R 46, 47. In humans, the high affinity IL-2R, comprising CD25, CD122 and CD132, is only expressed on CD56bright but not CD56dim NK cells. The stronger proliferation of CXCR3+ NK cells could be due to the higher expression of CD122 on CXCR3+ NK cells (data not shown). In addition, CD11b− NK cells are reported to proliferate faster

than CD11b+ cells in vivo30. Since a fraction of CXCR3+ NK cells was negative for CD11b, it is plausible that these cells proliferate more strongly. A major role of NK cells is to kill malignant tumor cells. Accumulation of NK cells in certain 3-oxoacyl-(acyl-carrier-protein) reductase tumor tissue is dependent on CXCR3 expression and the presence of IFN-γ 28. In this context, CXCR3+ NK cells are probably important for immunosurveillance, since these NK cells are also more potent IFN-γ producers than CXCR3− NK cells when stimulated with IL-12 and IL-18. Regarding cytotoxicity, specific lysis of YAC-1 target cells by CXCR3− NK cells was twice as high as by CXCR3+ NK cells. Degranulation corresponded well to this result in several compartments, corroborating the specific role of CXCR3− NK cells in terms of cytolytic ability.

It is early days in the study of KIR alleles but one trusts that the finding of selleck kinase inhibitor the new alleles can be independently confirmed (sequencing of alleles of the KIR genes is problematic because of similarities in the sequences of alleles from different genes and the size of the introns making it difficult to sequence from genomic DNA) and their possible clinical significance can be ascertained before we find ourselves in the same situation as for HLA alleles. There, 40% of HLA alleles have never been reported again after the report of their

initial sequence in one individual.57 A report of allele frequency data in a Japanese population showed that for the KIR genes KIR2DL1, KIR2DL2/2DL3, KIR2DL4, KIR3DL1/S1, KIR3DL2 and KIR2DS4, one allele at each gene was at a very high-frequency (44–89%) compared with the next frequent allele.58 This is not the case in many other populations,55 emphasizing the conclusion reached by Parham and colleagues of the skewed distribution of KIR variants in the Japanese population, which reflected a distinct history of directional and balancing selection.58 Linkage disequilibrium has been reported between the alleles

in a study examining the alleles of KIR2DL1, -2DL3, -3DL1 and -3DL2 in 34 families.59 Strong linkage disequilibrium existed between KIR2DL1 and -2DL3 alleles in the centromeric half and between KIR3DL1 and KIR3DL2 alleles in the telomeric half, but these two sets of pairs had little linkage disequilibrium between them and appeared to define the two halves of the KIR gene complex. This study was the Poziotinib first to show that in addition to gene Janus kinase (JAK) content, diversity of KIR was the result of allele polymorphism and the combination of gene content and allele differences resulted in the vast majority of individuals having different KIR genotypes. A further study

on individuals from North India determining only the alleles of KIR2DL1, -2DL3, -2DL5, -3DL1 and -3DL2 showed that all individuals had different KIR genotypes.43 In the Northern Ireland family study there were 188 (90%) different genotypes allowing for allele information. It is worth emphasizing that the Northern Ireland population is very homogeneous and drawn from a Caucasian population of 1·5 million, with very little immigration. Some alleles of the framework genes occurred more frequently on B haplotypes than A haplotypes Most notable of these was the occurrence of KIR2DL4*00501 on 43·6% of B but absent from A and KIR3DL2*007 on 43·6% of B but only 1·3% of A. In those genes that have been thought to be on A haplotypes (KIR2DL1, -2DL3, -3DL1, -2DS4) but that we found at a high occurrence on B haplotypes, there was little difference in the frequency of specific alleles on an A compared to a B haplotype, except the absence of KIR2DL1*00401 on A haplotypes, this allele being the most common allele of KIR2DL1 on B haplotypes at 27·7%.

Intradialytic changes in protein concentrations were assessed using the Wilcoxon matched-pairs signed rank test. Pearson’s correlation coefficients were calculated to assess the association serum this website Fet-A or serum RR and other baseline variables. Two-tailed P-values of <0.05 were considered significant. All analyses were

performed with spss version 20 (IBM Corporation, Chicago, IL, USA). One hundred and seven participants were recruited to the study, comprising 11 patients with pre-dialysis CKD (CKD group), 18 undergoing peritoneal dialysis (PD group), 36 prevalent haemodialysis patients (HD group), six patients with CUA on HD, 13 with chronic inflammatory disease but normal renal function (CID group) and 24 healthy adults (control group). Group characteristics are summarized in Table 1. Medication use at recruitment is shown in Table S1. Mean dialysis vintage was significantly longer in HD patients (68 ± 8 months) compared with PD patients (12 ± 3 months) (P < 0.001). Serum Fet-A RR remained below the limit of quantification (<4.7%) for all subjects in the healthy control group. Conversely, serum Fet-A RR levels were detectable in all patients in CKD, PD and HD groups and majority of patients with CID (11 of 13). As shown in Figure 1A, serum Fet-A RR were higher in the HD group compared with PD, CKD and CID groups.

Fet-A RR were also higher in PD patients compared with CKD and CID groups. CKD and CID groups, on the other hand, did not differ significantly in terms of Fet-A RR. The six patients with CUA had the highest mean Fet-A RR of 69% compared with only 37% in those on dialysis but without CUA (P < 0.001). Compared with the control group, serum total Fet-A

Daporinad cell line concentrations were lower in CKD, PD and HD groups, as well as in the CID group. CID, CKD, PD and HD groups did not differ significantly with respect to serum total Fet-A concentrations (Fig. 1B). Serum CRP concentrations were significantly higher in CID, PD and Loperamide HD groups compared with healthy controls. The CKD group had lower CRP concentrations than CID, PD and HD groups (Fig. 1C). Pre- and post-HD samples were available in 15 patients. Post-HD serum Fet-A and CRP concentrations were corrected for haemoconcentration according to changes in BW. During dialysis, median BW decreased from 76.2 kg (58.8–88.5) to 74.1 kg (57.0–85.5) after HD (P = 0.007). Figure 2 depicts the intradialytic changes in serum CPP, Fet-A and CRP concentrations. Post-HD serum Fet-A RR were significantly lower than pre-HD levels (P < 0.001). Serum total Fet-A and CRP concentrations also reduced during dialysis, but proportionately less than serum Fet-A RR. Uncorrected intradialytic changes in serum Fet-A and CRP concentrations are presented in Table S2. Correlational analysis of serum total Fet-A concentrations and Fet-A RR in combined CID, CKD, PD and HD groups (n = 83) is shown in Table 2. Serum Fet-A concentrations were inversely correlated with serum Fet-A RR (r = −0.242, P = 0.

© 2012 Wiley Periodicals, Inc. Microsurgery,

2012. “
“Nicotine causes ischemia and necrosis of skin flaps. Phosphodiesterase-5 (PDE-5) inhibition enhances blood flow and vasculogenesis. This study examines skin flap survival in rats exposed to nicotine that are treated with and without PDE-5 inhibition. Eighty six rats were divided into five groups. Group 1 received saline subcutaneous (SC) once per day. Group 2 received nicotine SC 2 mg/kg day. Group 3 received sildenafil Everolimus solubility dmso intraperitoneal (IP) 10 mg/kg day. Group 4 received nicotine SC 2 mg/kg and sildenafil IP 10 mg/kg day. Group 5 received nicotine SC 2 mg/kg day and sildenafil IP 10 mg/kg two times daily. After 28 days of treatment, modified McFarlane flaps were created, silicone sheets were interposed, and flaps were sutured. Photographs were taken on postoperative days 1, 3, and 7 and fluorescence angiography was used on day 7, both to evaluate for skin flap necrosis.

Rats were euthanized and flaps were harvested for Vascular Endothelial Growth Factor (VEGF) Western blot analysis. EPZ015666 in vivo Images were analyzed by three blinded observers using ImageJ, and necrotic indices were calculated. The nicotine and PDE-5 inhibition twice-daily group showed a 46% reduction in flap necrosis when compared to saline only (P < 0.05) and a 54% reduction when compared to nicotine only (P < 0.01). Fluorescence angiographic image from analysis revealed reductions in flap necrosis (P < 0.01). VEGF analysis trended toward increased VEGF for all sildenafil-treated groups (P > 0.05). PDE-5 inhibition exhibits a dose-dependent reduction in skin flap necrosis in rats exposed to nicotine. This suggests that PDE-5 inhibition may mitigate the ill effects of smoking on skin flaps. © 2014 Wiley Periodicals, Inc. Microsurgery 34:390–397, 2014. “
“Nerve regeneration after surgical reconstruction is far from optimal,

and thus effective strategies for improving the outcome of nerve repair are being sought. In this experiment, we verified if postoperative intraperitoneal melatonin (MLT) administration after intraoperative platelet gel application improves peripheral nerve regeneration. In adult male rats, 1-cm long sciatic nerve defects were repaired using four different strategies: autologous nerve graft repair followed by MLT (NM, n = 5), collagen conduit repair followed by MLT (CM, n = 5), platelet gel-enriched collagen conduit repair followed by MLT (CGM, n = 6), and platelet gel-enriched collagen conduit (CG, n = 5) repair followed by no substance administration. Sham operated animals were used as controls (Cont, n = 5). Ninety days after surgery, the nerve regeneration outcome was comparatively assessed by means of electrophysiological and stereological analysis. Electrophysiology revealed no significant differences between the experimental and the sham control groups.

Corticosteroid-treated hosts, however, are more likely to have tissue damage and necrosis caused by a defective, but exuberant inflammatory reaction to Aspergillus hyphae in the lung, which could theoretically alter classic patterns of dissemination.[27] Therefore, the changes in the predominant underlying immunosuppression likely contributed to the changing prevalence and pattern of IFIs observed at autopsy.[9] Although invasive moulds continue to be the predominant IFIs in haematological malignancy patients, the prevalence of Aspergillus infections decreased substantially in the last 5 years whereas the frequency

of Mucorales infections increased slightly. The increase in mucormycosis relative to aspergillosis in this population has been partially attributed to the increased use of echinocandins and voriconazole, which have good activity against Aspergillus spp., PD0325901 but limited or no activity against Mucorales.[28] However, decreased early mortality due to aspergillosis may allow patients to survive longer and accumulate risk factors (i.e. hyperglycaemia, iron overload) or increased environmental exposures that may favour the development of mucormycosis.[4-6, 28] Nevertheless, the increase in mucormycosis is concerning in light of the higher mortality rates in patients infected with non-Aspergillus

moulds including mucormycosis and fusariosis. More than half of the invasive mould infections in this autopsy survey were disseminated, STA-9090 chemical structure Interleukin-3 receptor accounting for the involvement of almost every organ in the autopsy examination. Beyond the sinopulmonary tract and central nervous system, moulds frequently disseminated to unusual sites such as the heart, gastrointestinal tract, liver, spleen and kidneys, which are considered to be common sites for dissemination of Candida infections.[18, 29] Indeed, our data suggest that over the last 10 years of the study, moulds were a more common cause of hepatosplenic lesions and infections involving the heart and kidneys

than yeast. The changes in invasive candidiasis at autopsy over the 20 year study period mirror the changing epidemiology that has been described in multiple studies,[1, 3, 11, 30, 31] namely a decrease in disseminated and hepatosplenic infections following the introduction and widespread use of fluconazole prophylaxis in the haematologic malignancy population. Candida invasion of the lung was frequently reported at autopsy in our patients despite the rare clinical occurrence of Candida pneumonia.[32] It is not clear whether this dissemination to the lung represents true infection represents true infection, or is an artifact of respiratory colonisation or post-mortem seeding.