Adult neurogenesis, a dramatic form of adult brain circuitry plasticity, has been implicated in physiological brain function and appears to be of pivotal importance for certain forms of learning and memory. In selleck inhibitor addition, failing or altered neurogenesis has been associated with a variety of brain diseases such as major depression, epilepsy and age-related cognitive decline. Here we review recent advances in our understanding of the basic

biology underlying the neurogenic process in the adult brain, focusing on mechanisms that regulate quiescence, proliferation and differentiation of NSPCs. In addition, we discuss how neurogenesis influences normal brain function, and in particular its role in memory formation, as well as its contribution to neuropsychiatric diseases. Finally, we evaluate the potential of targeting endogenous NSPCs for brain repair. The brain is challenged

every day by new experiences that have to be integrated into previously acquired knowledge and skills. Changes in neural function and subsequent connectivity are referred to as neural plasticity. It was believed for a long time that experience-induced changes of neural networks could only affect existing neuronal cells (i.e. cells that were generated during embryonic or early postnatal development). This central dogma was based on the idea that the brain is too complex an organ to allow for the generation and subsequent integration

of newborn neurones, especially in the adult. However, initial AZD6244 ic50 evidence dating back to the 1960s, which was debated for decades and finally accepted in the mid-1990s, showed that the STK38 adult mammalian brain contains substantial numbers of neurogenic neural stem/progenitor cells (NSPCs) that retain the ability to generate new neurones throughout life [1–4]. Thus, these seminal findings challenged previously held concepts about brain function and added a novel level of complexity to our understanding of adult neural plasticity. However, the process of adding new neurones into the preexisting neural circuitry, called adult neurogenesis, is not widespread throughout the brain but rather limited to two main neurogenic areas: the subventricular zone (SVZ) lining the lateral ventricles where NSPCs divide and give rise to cells that migrate along the rostral migratory stream (RMS) towards the olfactory bulb (OB) where they differentiate into distinct types of olfactory neurones; and the hippocampal dentate gyrus (DG) where NSPCs generate cells that differentiate into newborn granule cells (substantial amounts of neurogenesis have been identified in these two brain regions in adult rodents and non-human primates; the evidence for adult neurogenesis in humans will be discussed below) [5–7].

15–0.4 Hz, which

is the frequency interval of respiratory function; and (5) 0.4–1.6 Hz, which contains the heart beat frequency. Systemic hyperinsulinemia has been shown to affect microvascular vasomotion by increasing endothelial and neurogenic activity in skin and muscle [19,100], and that particularly the contribution of endothelial and neurogenic selleck screening library activity to microvascular vasomotion is impaired in obese, insulin-resistant individuals [23]. Local hyperinsulinemia during cathodal iontophoresis of insulin, on the other hand, affects microvascular vasomotion by increasing myogenic activity [91]. Similarly, rat muscle studies showed the main increase due to insulin to be myogenic [86]. Most studies of the effect of insulin on microvascular function have been conducted Trametinib order with the euglycemic, hyperinsulinemic clamp technique, i.e., under steady-state hyperinsulinemia. However, physiologically, hyperinsulinemia is usually

transient and dynamic, such as after a glucose load and after a meal, and is then accompanied by changes in circulating concentrations of glucose, amino acids, and gut and pancreatic peptides, which are not replicated by the clamp technique. If insulin’s effects on microvascular function play a physiological role in regulating insulin-mediated glucose uptake, such effects should be demonstrable not only during steady-state hyperinsulinemia but also after a meal. In addition, any such effects would be expected to be impaired in obese (insulin-resistant) individuals as compared with (insulin-sensitive) healthy controls. Interestingly, obesity has been shown to blunt changes in microvascular vasomotion specifically in the endothelial and neurogenic domain after a mixed meal (Figure 2) [56]. Obesity has also been shown to impair microvascular recruitment in human skeletal Tacrolimus (FK506) muscle after a mixed meal [58]. It is presently unknown whether microvascular vasomotion and capillary recruitment may be directly related, but preliminary

data suggest that insulin-induced changes in the neurogenic domain of vasomotion are associated with insulin-induced capillary recruitment (MP de Boer, unpublished data). Finally, insulin TET is a third potential site for regulating insulin delivery [6]. Recent in vivo and in vitro findings suggest that insulin crosses the vascular endothelium via a trans-cellular, receptor-mediated pathway, and emerging data indicate that insulin acts on the endothelium to facilitate its own TET [115]. It is still unclear whether capillary recruitment and TET of insulin may be related or may function independently. All together, these data illustrate the importance of the microcirculation in regulating nutrient and hormone access to muscle, and raise the possibility that any impairment in capillary recruitment may cause an impairment in glucose uptake by muscle.

WZW is the corresponding author. All authors read and approved the final manuscript. The authors declare that they have no competing interests. “
“Although periodontal tissue is continually challenged by microbial plaque, it is generally maintained in a healthy state. To understand the basis for this, we

investigated innate antiviral immunity in human periodontal tissue. The expression of mRNA encoding different antiviral proteins, myxovirus resistance A (MxA), protein kinase R (PKR), oligoadenylate synthetase Mitomycin C mouse (OAS), and secretory leukocyte protease inhibitor (SLPI) were detected in both healthy tissue and that with periodontitis. Immunostaining data consistently showed higher MxA protein expression in the epithelial layer of healthy gingiva as compared with tissue with periodontitis. Human MxA is thought to be induced by type I and III interferons (IFNs) but neither cytokine type was detected in healthy periodontal tissues. Treatment in vitro of primary human gingival epithelial cells (HGECs) with α-defensins, but not with the antimicrobial peptides β-defensins or LL-37, led to MxA protein expression. α-defensin was also detected in healthy periodontal tissue. In addition, MxA in α-defensin-treated HGECs was associated with protection against avian influenza H5N1 infection and silencing of the MxA gene using MxA-targeted-siRNA abolished this antiviral activity. To our knowledge, this is the first study to uncover

a novel pathway of human MxA check details induction, which is initiated by an endogenous antimicrobial peptide, namely α-defensin. This pathway may play an important role in the first line of antiviral ICG-001 defense in periodontal tissue. Periodontal tissue is a tooth-supporting structure, which includes gingiva, periodontal ligaments, cementum, and alveolar bone. Chronic inflammation of the periodontal tissue, periodontal disease, is one of the most common inflammatory diseases in humans. The advanced form of the disease, periodontitis, with severe bone destruction may cause tooth loss. The etiologic importance

of bacteria in periodontal disease has been well recognized. Bacterial plaque biofilms continually form on the tooth surfaces adjacent to gingiva. Recent studies have proposed that viral co-infection could enhance the development and progression of periodontitis [[1, 2]]. Detection of herpes simplex virus (HSV) types 1 and 2, human cytomegalovirus (CMV), Epstein-Barr virus (EBV), and human immunodeficiency virus (HIV), have been reported in dental plaque biofilm, gingival crevicular fluid, and periodontitis tissue specimens [[3]]. In healthy periodontal specimens, some viral deoxyribonucleic acid (DNA) can also be found, but generally at lower levels than in periodontitis [[4-6]]. Even so, the precise role of viruses in periodontal disease remains unclear. Periodontal tissue is continually exposed to bacterial plaque; therefore an effective innate immune response is critical to maintain homeostasis.

These transitional cells then differentiate into either MHC class I (MHCI)-specific CD8+ single positive (CD8 SP) or MHC class II (MHCII)-specific CD4+ single positive (CD4 SP) thymocytes (reviewed in 4). Several proteins have been implicated in the regulation of thymic development and positive selection (reviewed in 5–7). However, the process

of positive selection remains poorly understood. Cylidromatosis tumor suppressor (CYLD) is one of the proteins that have been implicated in the regulation of thymocyte selection. It is the product of a tumor suppressor gene (Cyld) that has been implicated in the development of a number of human malignancies (reviewed in 8). CYLD is a negative regulator of the NF-κB and MAPK pathways. GSK2118436 It was originally implicated in

thymocyte development by the demonstration Palbociclib datasheet of impaired SP thymocyte development in mice bearing null alleles 9. In addition, CYLD has been implicated in the regulation of peripheral T-cell homeostasis and in NKT and regulatory T-cell development 10–12. Recent studies from our lab uncovered CYLD’s involvement in the regulation of thymocyte positive selection in an NF-κB essential modulator (NEMO)-dependent manner 13. More specifically, thymocytes carrying a homozygous deletion of Cyld exon 9 (CyldΔ9) that results in the truncation of the deubiquitinating domain were blocked at the double dull stage and exhibited an increased propensity to die by apoptosis 13. The defective selection of CYLD-deficient thymocytes was restored upon concomitant inactivation of NEMO. These findings established for the first time a definitive functional

association between CYLD and NEMO in vivo, which is essential for the optimal selection of thymocytes. However, since NEMO regulates NF-κB and JNK activities 14, 15, both of which have been implicated in the process of thymocyte deletion 16, 17, the exact mechanism that underlies the defective selection of CYLD-deficient thymocytes remains unclear. In order to investigate this process further, IκB-kinase 2 (IKK2), which is the principal mediator ADAMTS5 of canonical NF-κB activation, was concomitantly inactivated with CYLD in thymocytes in order to evaluate specifically the contribution of NF-κB in CYLD-mediated selection of thymocytes. Mice with a thymocyte-specific truncation of the catalytic domain of CYLD were generated by crossing Cyldflx9/flx9 mice to LckCre-transgenic mice as previously described 13. The LckCre-Cyldflx9/flx9 mice were crossed with mice carrying a conditionally targeted Ikk2 allele (Ikk2flx/flx). More specifically, in Ikk2flx/flx mice, a premature stop codon can be conditionally introduced in the Ikk2 open-reading frame by Cre-mediated deletion of exons 6 and 7 18. The Ikk2flx/flx mice have been already used to evaluate the function of IKK2 in T-cell development, homeostasis and function 19. The double mutant mice (LckCre-Cyldflx9/flx9-Ikk2flx/flx) were viable, fertile and showed no obvious abnormalities.

Cumulative

pressure steps showed higher linearity in ΔMBV than that induced by discontinuous steps. The new NIRS variables we report could be a practical bench-to-bedside tool to assess venous driving pressure for systemic perfusion and measure changes in GDC-0068 in vivo Vu within the microvascular bed. “
“Obese subjects exhibit decreased exercise capacity (VO2max). We have shown that vascular KATP channel mediates arteriolar dilation to muscle contraction. We hypothesize that exercise capacity is decreased in obesity due to impaired vascular KATP function. The VO2max was measured in LZR and OZR by treadmill running before and following treatment with the KATP blocker glibenclamide i.p. One week later, the spinotrapezius muscle was prepared for in vivo microscopy. Arcade arteriolar diameters were measured following muscle contraction or application of the KATP opener cromakalim before and after glibenclamide application.

In additional animals, LZR and OZR were treated with apocynin for five weeks. VO2max and arteriolar dilation experiments Olaparib datasheet were repeated. The OZR exhibited decreased VO2max, functional and cromakalim-induced vasodilation as compared with LZR. Glibenclamide had no effect on VO2max and functional vasodilation in OZR, but significantly inhibited responses in LZR. Vascular superoxide levels and NADPH oxidase activity were increased in OZR, but reduced in apocynin-treated OZR. Apocynin increased the VO2max, functional and cromakalim-induced vasodilation in OZR with no effect in LZR. Exercise capacity is dependent on vascular KATP channel function. The reduced exercise capacity in OZR appears to be due in part to superoxide-mediated impairment in vascular KATP function. “
“Hypertension is characterized by microvascular remodeling resulting in increased wall/lumen ratio and elevated microvascular stiffness. Aiming MRIP to transform the measurement of macrovascular stiffness into a microvascular environment we introduce a noninvasive method to assess rPWV. rPWV alterations in early hypertension are investigated in detail. The developed methodology is compared with its possible computational alternatives. Time dependent alterations of retinal arterial diameter

were assessed noninvasively by the DVA in 65 male normoalbuminuric normotensive to mildly hypertensive subjects (age: 28.7 ± 6.0 years). rPWV was computed using three different methods. “Method 1” used filtration at HR, “Method 2” filtered at higher HR multiples, and “Method 3” used in addition, linear fit for data averaging. Method 2” and “Method 3” applying filtration at high HR multiples showed strong associations with systolic BP throughout the cohort (r = 0.49, r = 0.63, p < 0.001). Based on the highest association, “Method 3” was proposed to characterize rPWV. Hypertensive patients showed higher rPWV (1243 ± 694 RU/sec) than subjects with high-normal BP (786 ± 486 RU/sec, p < 0.01) or normotensive subjects (442 ± 148 RU/sec, p < 0.001).

In addition, residue MOG113–127 was found to be a B-cell epitope, suggesting that this may be a useful adjunct for the H 89 solubility dmso induction of EAE as well as for immunological studies

in C57BL/6 mice, which are increasingly being used to study immune function through the use of transgenic and gene knockout technology. Multiple sclerosis (MS) is an immune-mediated, demyelinating and neurodegenerative disease of the central nervous system (CNS).[1] These aspects of MS can be modelled using experimental autoimmune encephalomyelitis (EAE) in animals.[2] EAE can be induced following immunization with a variety of myelin proteins,[2] notably with CNS-specific antigens such as proteolipid protein and myelin oligodendrocyte glycoprotein (MOG).[2, 3] Whereas proteolipid protein, an extremely hydrophobic protein, is the major myelin protein in CNS myelin, MOG is a minor CNS myelin protein present as a transmembrane protein expressed exclusively on the surface of oligodendrocytes and myelin. Despite comprising only 2·5% of the myelin proteins,[4] MOG is a powerful encephalitogen inducing EAE in a range of species including mice, rats and monkeys.[2-5] The full-length protein contains 218 amino acids that form a single extracellular region containing an immunoglobulin-like domain (residues 1–125), anchored

by a hydrophobic transmembrane domain (residues 126–146), an intracytoplasmic domain (residues 147–181), a second hydrophobic transmembrane domain (residues Rucaparib concentration 182–202) and another extracellular domain (residues 203–218). Many immunological studies in EAE and MS make use of recombinant proteins

representing the extracellular immunoglobulin-like domain of MOG, which is expressed on the surface of oligodendrocyte and myelin and is therefore readily available for recognition by autoreactive antibody responses.[2, 3, 6] However, the use of recombinant protein and peptides fails to address the possible pathogenic role of the full-length myelin-derived protein, expression of conformational epitopes, peptide targets within the transmembrane and intracytoplasmic medroxyprogesterone domains as well as post-translational modifications.[7, 8] More recently, several of these aspects have been addressed with the use of myelin from wild-type (WT) and MOG-deficient (MOG−/−) mice.[9] Immunization with myelin from these animals demonstrates that immune responses to MOG in myelin can be crucial for chronic demyelinating EAE in mice and common marmosets.[4, 5] Having established that MOG-specific peptides can induce EAE in rodents,[3, 10] an important finding arising from the early studies on the encephalitogenic potential of MOG was the identification of an epitope of human MOG35–55 (hMOG35–55) that induced EAE in C57BL/6 mice.

5% of the total media volume. Our results indicate that this low concentration of DMSO does not significantly alter IFN-γ production compared to assays to which no DMSO was added (data not shown). RT-PCR analysis of IFN-γ transcription.  NK92 effector cells and K562 target cells from some IFN-γ release assays were retained and used to generate cDNA to analyse IFN-γ transcription. Cells

were resuspended in 200 μl RNAStat60 (Ambion, Austin, TX, USA) mixed with chloroform and centrifuged to separate total RNA from cellular debris. Precipitated total RNA was used as RT-PCR template to generate cDNA using Qiagen Omniscript RT Kit (Qiagen, Valencia CA, USA). cDNA was analysed by PCR for IFN-γ expression. GAPDH primers were also used as a control. The primers used were hIFN-γ 109 FP 5′ – ATG AAA TAT ACA AGT TAT ATC TTG GCT TT – 3′ [20] hIFN-γ 474 RP 5′ – CGA ATA ATT AGT buy CAL-101 CAG CTT TTC GAA G – 3′ [21] GAPDH FP 5′ – ATG ACA TCA AGA AGG TGG TG – 3′ GAPDH RP 5′ – CAT ACC AGG AAA TGA GCT TG – 3′ PCR products were analysed by electrophoresis on a 1% agarose

gel with ethidium bromide and visualized by UV fluorescence. IFN-γ PCR product is approximately 370 bp. GAPDH PCR product is approximately 177 bp. Paraformaldehyde fixing.  To prevent the release ACP-196 in vitro of phospho-proteins from K562 when the NK92:K562 cell mixture was subjected to lysis buffer, all K562 target cells were fixed with paraformaldehyde prior to co-incubation with NK92. Published data demonstrates that detergent lysis is prevented by fixing cells in this manner [22–24]. Following the protocol described by Djeu’s Group, K562-CD161 and K562-pCI-neo target cells were resuspended in 4% paraformaldehyde (Fisher Scientific, Pittsburgh, PA, USA) and incubated on ice for 30 min. They were subsequently washed four times with ice cold PBS before being resuspended in an appropriate volume of media for the NK92 co-incubation assay. This paraformaldehyde fixing prevents the detection of K562 intracellular

protein by SDS-PAGE and western blot [22–24]. To confirm that CD161 is still functional after paraformaldehyde fixing, K562-CD161 and K562-pCI-neo fixed target cells were additionally used as target cells for NK92 in overnight Palbociclib purchase IFN-γ production assays. Phosphorylation assay.  To stimulate phosphorylation of LLT1 downstream signals, NK92 cells that were rested overnight without IL-2 were co-incubated with an equal number of fixed K562 target cells for 5–30 min. Once the incubation was complete, the cell mixture was quickly centrifuged and resuspended in Cell Signalling 1× Cell Lysis Buffer on ice for 5 min. Lysate was then centrifuged for 15 min at maximum speed at 4 °C to remove all cellular debris. Protein levels in supernatants were estimated via spectrophotometry using Bradford reagent to ensure equal loading on SDS-PAGE gels.

The present work presents evidence that a progressively growing, endogenous tumor indeed fails to activate NK-cell effector functions. Escape from NK-cell surveillance seems

to be more complex than the hypothesis of failing priming or failing triggering might suggest. Possibly, NK cells are exhausted as a consequence of prolonged activation, as it was described for T cells 44. Alternately, developing tumors might actively paralyze NK cells. These observations should be considered when establishing, e.g. approaches Cobimetinib manufacturer of adoptive NK-cell transfer. All cell lines were cultured in RPMI 1640 (Invitrogen, Karlsruhe, Germany) medium supplemented with 5% heat-inactivated FBS, 2 mM L-Glutamine, 100 U/mL penicillin and streptomycin, non essential aa, and 50 μM 2-ME. Cells were kept

at 37°C in a humidified 5% CO2 atmosphere. A20 and MPC11 are BALB/c-derived B-cell lymphoma cell lines 45, 46. The variant A20low expressing reduced levels of MHC class I was generated by transfection of A20 with an mCMV-derived gene 6. The murine lymphoma cell line YAC-1 served as a target for NK-cell killing in cytotoxicity assays 47. DC were generated exactly as previously described 22. λ-myc cell lines myc-B, myc-E and 291S were generated by seeding primary lymphoma cells from λ-myc mice on irradiated MRC-5 fibroblasts as a feeding layer. After about 2 wk of culture, cells were able INCB024360 concentration to grow independently. All animals were kept under specific pathogen-free conditions in our animal facility. C57BL/6 and BALB/c WT mice were purchased from Bommice (Ry, Denmark). λ-myc mice 29 are of C57BL/6 origin and were bred in our own facility. All animal experiments were in accordance with relevant regulations and had been approved by the Regierung von Oberbayern. Groups of at least six age-matched mice were used for experiments. Animals were treated with 10 nMol

CpG-ODN 1668 (Metabion, Martinsried, Germany) that was injected i.p. in 1- to 2-wk intervals 6 or received 5×105 DC subcutaneously as described earlier 22. NK-cell depletion was done by using anti-asialo GM1 Ab (Wako, Neuβ, Germany). 100–300 μL were administered i.v. and i.p. 1 day before each CpG-ODN injection Florfenicol in λ-myc mice; 300 μL were given i.p. 1 day before as well as 2 and 9 days after challenge with myc-B tumor cells in WT mice. NKT cells were not affected by treatment with anti-asialo GM1. In total, 104 to 105 myc-B, myc-E, 291S or MPC11 cells or 106 A20 or A20low cells were injected i.v. Phenotyping of NK cells was done by labeling with the following mAb: CD49b (DX5, BD Pharmingen, Heidelberg, Germany), CD45R (RA3-6B2, BD Pharmingen), NKG2D (CX5, eBioscience, San Diego, USA), Ly49D (4E5, BD Pharmingen), Ly49I (YLI-90, BD Pharmingen), CD69 (H1.

2F). Since FcεRI-mediated mitogen-activated protein kinases (MAPKs) activation leads to gene transcription of several cytokines 19, 20, we next examined the levels of phosphorylation of p38 MAPK in DNP-HSA-activated and desensitized cells (see Fig. 2F). As expected by the low levels of TNF-α and IL-6 production, p38 MAPK phosphorylation was inhibited by rapid desensitization, indicating that molecular events leading to cytokine gene transcription were inhibited during rapid desensitization. Because the duration of desensitization may depend on the presence of bound and soluble antigen, we determined the duration of, and antigen requirements for, maintaining hypo-responsiveness after

Ulixertinib purchase desensitization. Cells challenged with 1 ng DNP-HSA at 10 min, 2 h and 4 h after desensitization, remained hypo-responsive with a 20% β-hexosaminidase release (see Fig. 3A, first bar of each time group of bars). Treatment of desensitized cells with ionomycin at 10 min, 2 h or 4 h after desensitization, resulted in high levels of β-hexosaminidase release (see Fig. 3A,

second bar of each time group of bars), indicating that desensitized cells were not mediator-depleted. Further time points were not pursued due to diminishing cell viability after 6 h (from 91 to 83% viability 4 h after desensitization (100 min)). This decrease in cell viability was attributed to low volume (106 cells in 50–100 μL) and IL-3 and CO2 depletion. We then considered the Sirolimus clinical trial possibility that desensitized BMMCs could remain hypo-responsive to further stimulation due to the excess of soluble antigen. Washed and non-washed desensitized cells responded similarly to challenge (see Fig. 3B), indicating that once hypo-responsiveness was achieved the presence PRKACG of soluble antigen was not required for maintaining desensitization. Internalization of antigen/IgE/FcεRI complexes has been demonstrated after cell activation 21, 22, and it has been suggested that mast cell hypo-responsiveness to low antigen

doses is due to internalization of antigen-bound receptors 12. We wanted to determine the fate of the antigen/IgE/FcεRI complex with desensitization. We analyzed surface expression of FcεRIα and IgE in rapid-desensitized cells, in cells challenged with 1 ng DNP-HSA or with 1 ng HSA, and in non-sensitized cells. Surface expression levels of FcεRIα and IgE in desensitized cells were similar to those of cells challenged with 1 ng HSA and significantly higher than in activated cells (see Fig. 4A), indicating the impairment of internalization of IgE and FcεRIα. Since most of the IgE/FcεRI complexes remained on the cell surface, we sought to determine whether anti-IgE could crosslink free IgE on desensitized cells. DNP-desensitized cells released β-hexosaminidase when treated with anti-IgE (see Fig. 4B), indicating that unbound IgE was available for crosslinking and remained accessible.

glabrata (24%), C. tropicalis (15%), C. krusei (13%) and C. parapsilosis (3%). Multiple Candida infections ranged between 3% and 15% of all autopsy cases with documented yeast infection whereas non-Candida yeast and yeast-like find more species (i.e. Trichosporon,

Rhodoturula, Saccharomyces cerevesiae) occurred in 4–10% of cases during the 20 year period. Interestingly, infections caused by Candida species with variable (C. glabrata) or non-susceptibility (C. krusei) to fluconazole decreased in the final 5 years of the study, whereas C. albicans and C. tropicalis infections increased. The pattern of organ involvement by IFIs differed depending on the fungal pathogen and type of underlying immunosuppression. Candida spp. were frequently detected by both culture and histopathology in the lung (79%), blood (37%), gastrointestinal tract (35%), kidney (34%),

liver (20%) and spleen (19%). Patterns of organ involvement did not differ significantly, Y-27632 mw however, among the isolated species. Patients with persistent neutropenia were more likely to have invasion of the kidney (P = 0.02) and heart (P = 0.02) compared with non-neutropenic patients. High-dose corticosteroid therapy did not appear to predispose to a specific pattern of organ involvement. The lungs were the most common site of infection for moulds, occurring in more than 90% of all infections. Aspergillus infections most frequently affected the lung (92%), central nervous system TCL (25%), heart (24%), kidney (15%) and gastrointestinal tract (15%). Aspergillus spp. were rarely (4%) isolated from blood cultures, and nearly all of the positive cultures were caused by A. terreus (60%) or A. flavus (40%). Compared with Aspergillus spp., Mucorales were more likely to be associated with invasion of the sinuses (23% vs. 5%, P = 0.007). Fusarium spp. were isolated frequently from the heart (63%), kidney (50%), spleen (50%) and bloodstream (40%). We also compared patterns of organ dissemination over the study period for the four most common monomicrobial infections detected at autopsy among patients with haematological malignancies. Significant reductions in

Candida dissemination to the spleen, kidney, heart, gastrointestinal tract and liver were observed over the 20 year study period, although Candida spp. dissemination to the liver rebounded back to a percentage observed in earlier periods of the study by 2004–2008 (Fig. 2). After 2003, moulds accounted for the majority of infections identified at autopsy in four of these five organs including the spleen, kidney, heart and gastrointestinal tract. To our knowledge, this is the largest single-institution study of autopsy proven IFI in patients with haematological malignancies spanning two decades. Collectively, these autopsy data support the findings of recent epidemiological surveys that have documented a declining prevalence of IFIs and associated mortality in this high-risk population.