Cryptococcus gattii Meningoencephalitis in an Immunocompetent Person 13 Months after Exposure

Abstract : A 53-year old immunocompetent Swiss female is described who developed severe meningoencephalitis due to infection with Cryptococcus gattii 13 months following exposure on Vancouver Island, Canada. Diagnosis was based on cerebrospinal fluid (CSF) examination, i.e., positive India-ink staining, positive latex particle agglutination, and positive culture. Species identification was performed by growth on L-canavanine-glycine-bromthymol blue medium and by sequencing of the intergenic and internal transcribed spacer regions of the rRNA genes. After initial therapy with fluconazole by which the patient did not improve, therapy was changed to amphotericin B and flucytosine and later to high-dose fluconazole and amphotericin B. Despite long-term treatment and external drainage of the CSF, the patient's condition improved only slowly. The patient was discharged after 132 days of hospitalizatio

ABA-Induced Vegetative Diaspore Formation in Physcomitrella patens

The phytohormone abscisic acid (ABA) is a pivotal regulator of gene expression in response to various environmental stresses such as desiccation, salt and cold causing major changes in plant development and physiology. Here we show that in the moss Physcomitrella patens exogenous application of ABA triggers the formation of vegetative diaspores (brachycytes or brood cells) that enable plant survival in unfavorable environmental conditions. Such diaspores are round-shaped cells characterized by the loss of the central vacuole, due to an increased starch and lipid storage preparing these cells for growth upon suitable environmental conditions. To gain insights into the gene regulation underlying these developmental and physiological changes, we analyzed early transcriptome changes after 30, 60, and 180 min of ABA application and identified 1,030 differentially expressed genes. Among these, several groups can be linked to specific morphological and physiological changes during diaspore formation, such as genes involved in cell wall modifications. Furthermore, almost all members of ABA-dependent signaling and regulation were transcriptionally induced. Network analysis of transcription-associated genes revealed a large overlap of our study with ABA-dependent regulation in response to dehydration, cold stress, and UV-B light, indicating a fundamental function of ABA in diverse stress responses in moss. We also studied the evolutionary conservation of ABA-dependent regulation between moss and the seed plant Arabidopsis thaliana pointing to an early evolution of ABA-mediated stress adaptation during the conquest of the terrestrial habitat by plants

Antimykotische Therapie der invasiven pulmonalen Infektion durch Scedosporium und Pseudallescheria spp. bei Mukoviszidose

Autre titre : Antimykotische Therapie der pulmonalen Infektion durch Scedosporien bei MukoviszidoseInternational audienc

Combined antifungal therapy is superior to monotherapy in pulmonary scedosporiosis in cystic fibrosis

Cystic fibrosis (CF) is characterised by chronic airway infection with bacteria and fungi. Infections caused by Scedosporium/Lomentospora species can occur and are difficult to treat. Moulds belonging to the genus Scedosporium/Lomentospora are detected most frequently in respiratory samples of patients with CF, next to Aspergillus spp. Our aim was to define pulmonary fungal infections due to Scedosporium/Lomentospora in CF and to study the antimycotic treatment. In this multicentre study (12 centres; duration January 2008 to December 2014) 31 patients with a lung infection caused by moulds of the genus Scedosporium/Lomentospora were included. 36 courses of antifungal treatment were documented. Scedosporium apiospermum sensu stricto accounted for 48.4% of cases. In 20/31 patients a therapeutic response under antimycotics (median duration 3.9 months) was achieved. Triple and double therapy was significantly more effective compared to monotherapy regarding FEV1, radiology, and symptoms. This data suggests that combined treatment is superior to monotherapy in patients with CF

Proposed nomenclature for Pseudallescheria, Scedosporium and related genera

As a result of fundamental changes in the International Code of Nomenclature on the use of separate names for sexual and asexual stages of fungi, generic names of many groups should be reconsidered. Members of the ECMM/ISHAM working group on Pseudallescheria/Scedosporium infections herein advocate a novel nomenclature for genera and species in Pseudallescheria, Scedosporium and allied taxa. The generic names Parascedosporium, Lomentospora, Petriella, Petriellopsis, and Scedosporium are proposed for a lineage within Microascaceae with mostly Scedosporium anamorphs producing slimy, annellidic conidia. Considering that Scedosporium has priority over Pseudallescheria and that Scedosporium prolificans is phylogenetically distinct from the other Scedosporium species, some name changes are proposed. Pseudallescheria minutispora and Petriellidium desertorum are renamed as Scedosporium minutisporum and S. desertorum, respectively. Scedosporium prolificans is renamed as Lomentospora prolificans

A novel BACE inhibitor NB-360 shows a superior pharmacological profile and robust reduction of amyloid-β and neuroinflammation in APP transgenic mice

BACKGROUND: Alzheimer’s disease (AD) is the most common form of dementia, the number of affected individuals is rising, with significant impacts for healthcare systems. Current symptomatic treatments delay, but do not halt, disease progression. Genetic evidence points to aggregation and deposition of amyloid-β (Aβ) in the brain being causal for the neurodegeneration and dementia typical of AD. Approaches to target Aβ via inhibition of γ-secretase or passive antibody therapy have not yet resulted in substantial clinical benefits. Inhibition of BACE1 (β-secretase) has proven a challenging concept, but recent BACE1inhibitors can enter the brain sufficiently well to lower Aβ. However, failures with the first clinical BACE1 inhibitors have highlighted the need to generate compounds with appropriate efficacy and safety profiles, since long treatment periods are expected to be necessary in humans. RESULTS: Treatment with NB-360, a potent and brain penetrable BACE-1 inhibitor can completely block the progression of Aβ deposition in the brains of APP transgenic mice, a model for amyloid pathology. We furthermore show that almost complete reduction of Aβ was achieved also in rats and in dogs, suggesting that these findings are translational across species and can be extrapolated to humans. Amyloid pathology may be an initial step in a complex pathological cascade; therefore we investigated the effect of BACE-1 inhibition on neuroinflammation, a prominent downstream feature of the disease. NB-360 stopped accumulation of activated inflammatory cells in the brains of APP transgenic mice. Upon chronic treatment of APP transgenic mice, patches of grey hairs appeared. CONCLUSIONS: In a rapidly developing field, the data on NB-360 broaden the chemical space and expand knowledge on the properties that are needed to make a BACE-1 inhibitor potent and safe enough for long-term use in patients. Due to its excellent brain penetration, reasonable oral doses of NB-360 were sufficient to completely block amyloid-β deposition in an APP transgenic mouse model. Data across species suggest similar treatment effects can possibly be achieved in humans. The reduced neuroinflammation upon amyloid reduction by NB-360 treatment supports the notion that targeting amyloid-β pathology can have beneficial downstream effects on the progression of Alzheimer’s disease

IL-22BP controls the progression of liver metastasis in colorectal cancer

BackgroundThe immune system plays a pivotal role in cancer progression. Interleukin 22 binding protein (IL-22BP), a natural antagonist of the cytokine interleukin 22 (IL-22) has been shown to control the progression of colorectal cancer (CRC). However, the role of IL-22BP in the process of metastasis formation remains unknown.MethodsWe used two different murine in vivo metastasis models using the MC38 and LLC cancer cell lines and studied lung and liver metastasis formation after intracaecal or intrasplenic injection of cancer cells. Furthermore, IL22BP expression was measured in a clinical cohort of CRC patients and correlated with metastatic tumor stages.ResultsOur data indicate that low levels of IL-22BP are associated with advanced (metastatic) tumor stages in colorectal cancer. Using two different murine in vivo models we show that IL-22BP indeed controls the progression of liver but not lung metastasis in mice.ConclusionsWe here demonstrate a crucial role of IL-22BP in controlling metastasis progression. Thus, IL-22 might represent a future therapeutic target against the progression of metastatic CRC

Cryptococcal meningitis: epidemiology, immunology, diagnosis and therapy.

HIV-associated cryptococcal meningitis is by far the most common cause of adult meningitis in many areas of the world that have high HIV seroprevalence. In most areas in Sub-Saharan Africa, the incidence of cryptococcal meningitis is not decreasing despite availability of antiretroviral therapy, because of issues of adherence and retention in HIV care. In addition, cryptococcal meningitis in HIV-seronegative individuals is a substantial problem: the risk of cryptococcal infection is increased in transplant recipients and other individuals with defects in cell-mediated immunity, and cryptococcosis is also reported in the apparently immunocompetent. Despite therapy, mortality rates in these groups are high. Over the past 5 years, advances have been made in rapid point-of-care diagnosis and early detection of cryptococcal antigen in the blood. These advances have enabled development of screening and pre-emptive treatment strategies aimed at preventing the development of clinical infection in patients with late-stage HIV infection. Progress in optimizing antifungal combinations has been aided by evaluation of the clearance rate of infection by using serial quantitative cultures of cerebrospinal fluid (CSF). Measurement and management of raised CSF pressure, a common complication, is a vital component of care. In addition, we now better understand protective immune responses in HIV-associated cases, immunogenetic predisposition to infection, and the role of immune-mediated pathology in patients with non-HIV associated infection and in the context of HIV-associated immune reconstitution reactions