Emerging infectious endocarditis due to Scedosporium prolificans: a model of therapeutic complexity.

Scedosporium prolificans is an emerging agent for severe infections. Although among the dematiaceous fungi Scedosporium is the most frequently isolated in blood cultures, Scedosporium endocarditis is rarely reported. We show herein a patient with acute leukaemia who developed S. prolificans endocarditis. Twelve cases were found in an extensive review of the English literature. In six cases (46%), there was predisposing heart conditions such as a prosthetic valve or an intracavitary device. Only 4 patients (31%) were immunocompromised hosts with haematologic neoplasia, solid-organ transplantation or acquired immunodeficiency syndrome (AIDS). Exposure to Scedosporium was observed in immunocompetent patients who developed infection while in the community. Scedosporium endocarditis occurred on both sides of the heart. Systemic and pulmonary emboli and other metastatic complications were seen in all of these patients. The overall mortality was 77% and, specifically, all of the immunocompromised hosts and 6 out of 7 patients with mitral or aortic valve endocarditis died. Patients with right-sided endocarditis associated with a removable intracardiac device exhibited a better prognosis. Scedosporium endocarditis, although still rare, is an emerging infection with an ominous prognosis. At the present time, valve replacement or the removal of cardiac devices plus combined antifungal treatment may offer the best possibility of cure.

Demographics, laboratory parameters and outcomes of 1061 patients with coronavirus disease 2019: a report from Tehran, Iran.

We aimed to determine the characteristics of coronavirus disease 2019 (COVID-2019) among the Iranian population. In this study, we collected and analysed the demographics, laboratory findings and outcomes of patients with COVID-19 who were admitted to Masih Daneshvari Hospital in Tehran, Iran between 20 February 2020 and 2 April 2020. Among 1061 patients, 692 (65.2%) were male and the median age was 55 years (interquartile range (IQR), 44-66 years). Totally, 129 (12.2%) patients died during hospitalization in the ward or intensive care unit. From the remaining 932 individuals, 46 (5.0%) were admitted to the intensive care unit and 886 (95.0%) were hospitalized in the ward. Those patients who died were significantly older than those hospitalized in the ward (p < 0.001). The median absolute number of lymphocytes was 1.2 × 103/µL (IQR 0.9 × 103 to 1.6 × 103/µL) and 708 (66.7%) patients had lymphopenia (absolute lymphocyte count <1500/µL). Among the laboratory tests, D-dimer, serum ferritin and albumin had the strongest correlations with mortality (r = 0.455, r = 0.412, r = -0.406, respectively; p < 0.001 for each one). In conclusion, laboratory findings could provide useful information with regard to the management of individuals with COVID-19.

Molecular identification, phylogenetic analysis and antifungal susceptibility patterns of Aspergillusnidulans complex and Aspergillusterreus complex isolated from clinical specimens.

OBJECTIVE: Aspergillus sections Terrei and Nidulantes are the less common causes of invasive aspergillosis and pulmonary aspergillosis (PA) in immunocompromised patients when compared to A. fumigatus and A. flavus. Identifying these fungi as the infectious agent is crucial because of the resistance to amphotericin B (AMB) and increased lethality. The aim of this study was to identify the molecular status, evaluate the genetic diversity and examine the antifungal susceptibility profile of the uncommon Aspergillus species. Forty-five uncommon Aspergillus species were identified based on the microscopic and macroscopic criteria. Then, the molecular identification was performed using the sequencing beta tubulin (benA) gene. In vitro antifungal susceptibility to amphotericin B (AMB), itraconazole (ITC), ravuconazole (RAV), voriconazole (VRC), caspofungin (CFG) isavuconazole (ISA) and posaconazole (POS) test was performed according to the CLSI M38-A2 guidelines. RESULTS: A. terreus was the most species detected, followed by A. nidulans, A. latus, A.ochraceus, and A. citrinoterreus, respectively. The analysis of the benA gene showed the presence of 12 distinct genotypes among the A. terreus isolates. The other species did not show any intraspecies variation. CFG exhibited the lowest MEC50/MIC50 (0.007µg/mL), followed by POS (0.125µg/mL), VRC, ITC, ISA (0.25µg/mL), RAV (0.5µg/mL), and AMB (8µg/mL). Among all the isolates, only 15.5% (7/45) were susceptible to AMB. CONCLUSION: Antifungal susceptibility pattern of the uncommon Aspergillus species is useful to improve patient management and increase knowledge concerning the local epidemiology. Moreover, this information is necessary when an outbreak dealing with drug-resistant infections occurs.

Micro-CT based finite element modelling and experimental characterization of the compressive mechanical properties of 3-D zirconia scaffolds for bone tissue engineering.

The present study aims at developing a computational framework with experimental validation to determine the mechanical properties of zirconia foams for bone tissue engineering. A micro-CT based finite element model that allows characterizing the mechanical property of such cellular structures is developed. Micro-CT images are filtered to vanish noises and smooth boundaries before constructing 3D zirconia foams using an adaptive Body-Centered Cubic background lattice. In addition to micro-CT images, the local material property at the scaffold struts is measured using a micro-indentation test, which shows a considerable difference with that of common zirconia owing to the manufacturing process. The computational model also takes the plastic deformation of material into account employing the Voce law, a nonlinear isotropic hardening law, as well as Von-mises yield criterion. Zirconia foams with different pore sizes are manufactured using the replica method and their mechanical properties determined experimentally. Such experimental outcomes are to validate and demonstrate the capability of the developed model, which can be used for pre-operational evaluations and preclinical tests of zirconia scaffolds. The stress magnitude and distribution within the scaffold as well as plastic strains and flow stress of the zirconia scaffold are computed and analysed. Using the proposed approach, a deep insight into the association of macroscopic behaviour of the scaffold to microscopic features, e.g. strut waviness, Plateau border, thickness variation of cells, irregularity, microstructural variability, imperfections and strut's material property associated with to the manufacturing procedure, can be gained.

Oncolytic activity of vesicular stomatitis virus in primary adult T-cell leukemia.

Treatments for hematological malignancies have improved considerably over the past decade, but the growing therapeutic arsenal has not benefited adult T-cell leukemia (ATL) patients. Oncolytic viruses such as vesicular stomatitis virus (VSV) have recently emerged as a potential treatment of solid tumors and leukemias in vitro and in vivo. In the current study, we investigated the ability of VSV to lyse primary human T-lymphotropic virus type 1 (HTLV-1)-infected T-lymphocytes from patients with ATL. Ex vivo primary ATL cells were permissive for VSV and underwent rapid oncolysis in a time-dependent manner. Importantly, VSV infection showed neither viral replication nor oncolysis in HTLV-1-infected, nonleukemic cells from patients with HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP), and in naive CD4(+) T-lymphocytes from normal individuals or in ex vivo cell samples from patients with chronic lymphocytic leukemia (CLL). Interestingly, activation of primary CD4(+) T-lymphocytes with anti-CD3/CD28 monoclonal antibody, and specifically with anti-CD3, was sufficient to induce limited viral replication and oncolysis. However, at a similar level of T-cell activation, VSV replication was increased fourfold in ATL cells compared to activated CD4(+) T-lymphocytes, emphasizing the concept that VSV targets genetic defects unique to tumor cells to facilitate its replication. In conclusion, our findings provide the first essential information for the development of a VSV-based treatment for ATL.

Interleukin 15-mediated induction of cytotoxic effector cells capable of eliminating Epstein-Barr virus-transformed/immortalized lymphocytes in culture.

BACKGROUND: Interleukin 15 (IL-15) activates cytotoxic lymphocytes and drives the expansion of memory T cells. Its role in immune control of virus-transformed cells and other tumor cells remains to be elucidated. We investigated the role of IL-15 in controlling Epstein-Barr virus (EBV)-transformed/immortalized lymphocytes in culture. EBV is a highly potent lymphocyte-transforming and opportunistic oncogenic herpesvirus associated with several human tumors. METHODS: Peripheral blood mononuclear cells (PBMCs) from healthy donors were infected with EBV and cultured with either IL-15 or IL-15 plus anti-IL-15 antibodies for 3-4 weeks. We monitored EBV-induced transformation by assessing the clearly visible cell clusters by microscopy and analyzing the expression of EBV-encoded latent membrane oncoprotein-1 (LMP-1) and the EBV nuclear antigen (EBNA) complex by immunoblotting and immunofluorescence techniques, respectively. We depleted EBV-infected cultures of PBMCs of specific effector cell populations to investigate the effector cells involved in mediating IL-15 effect. RESULTS: The presence of IL-15 resulted in the complete elimination of EBV-transformed cells in PBMC cultures. Western blot and immunofluorescence analyses performed 3-4 weeks after infection showed no detectable levels of LMP-1 and EBNA in IL-15-treated EBV-infected cultures, whereas IL-15-untreated EBV-infected cultures and IL-15/anti-IL-15-treated cultures expressed both proteins. IL-15 mediated its anti-EBV effect through early and late response mechanisms, i.e., by first activating natural killer (NK) cells and subsequently inducing cytolytic NK-T cells. The presence of anti-IL-15 neutralizing antibodies abrogated IL-15's effect on both mechanisms. CONCLUSION: In vitro, IL-15 mediated complete elimination of EBV-infected/transformed lymphocytes via successive activation of NK and NK-T cytotoxic effectors. If these in vitro findings reflect in vivo mechanisms, then IL-15 might be considered for cytokine-based immunotherapy in patients with EBV-associated lymphoproliferative disorders/malignancies.

Hydraulic theory for a debris flow supported on a collisional shear layer.

We consider a heap of grains driven by gravity down an incline. We assume that the heap is supported at its base on a relatively thin carpet of intensely sheared, highly agitated grains that interact through collisions. We adopt the balance laws, constitutive relations, and boundary conditions of a kinetic theory for dense granular flows and determine the relationship between the shear stress, normal stress, and relative velocity of the boundaries in the shear layer in an analysis of a steady shearing flow between identical bumpy boundaries. This relationship permits us to close the hydraulic equations governing the evolution of the shape of the heap and the velocity distribution at its base. We integrate the resulting equations numerically for typical values of the parameters for glass spheres. (c) 1999 American Institute of Physics.

DDT and immunological responses. 3. Reduced anaphylaxis and mast cell population in rats fed DDT.

Previous work showed that anaphylaxis, mast cell population, and tissue histamine content are reduced in guinea pigs given DDT injections. This study was intended to determine whether dietary intake of DDT causes similar effects. Rats immunized with diphtheria toxoid and fed diets containing DDT at 20 and 200 ppm levels for 31 days did not show effects on their serum antitoxin titers, but the numbers of metachromatically stained, histamine-containing mast cells in mesenteries were reduced: in the 20 ppm group by 46% and in the 200 ppm group by 61%. The severity of anaphylactic shock was also reduced in proportion to the DDT dietary levels, and, thus, the magnitude of mast cells. Apparently, daily dietary DDT intake above 2.2 mg DDT/kg of body weight alters the physiology of mast cells in the rat, and thus affects histamine-mediated reactions.

AIDS and the minority health care worker.

1. Large groups of health care workers, many of whom are among ethnic minorities with potential for occupational exposure to HIV/HBV, are generally underserved in training on prevention of occupational transmission of the viruses. 2. The inadequacy of training for indirect client care personnel appears to be one of the primary reasons for high rates of needlestick injuries and exposure to blood. 3. Training in appropriate infection control techniques can help reduce the uneasiness and fear among health care workers over occupationally-related HIV/HBV transmission.

The incidence of cross infections in Imam Reza hospital, Mashhad, Iran.

BACKGROUND AND OBJECTIVES: Cross Infections (CIs) are considered as a major public health problem worldwide. They cause delay in recovery, increased mortality and morbidity. The purpose of this study is to report the incidence of CIs in our teaching hospital during a 23-month period. MATERIALS AND METHODS: In this descriptive cross-sectional study, 76766 patients from 2009 to 2011 admitted to 17 wards of Imam Reza Hospital in Mashhad were studied for CIs. Patients' age, sex, site of infection, ward of hospitalization and type of microbial infections were collected and analyzed by SPSS 16.0. CONCLUSION: Results of the present study showed that the incidence of CIs was low (i.e.<1%) in our hospital and Acinetobacter (25.8%, n = 176) was the most frequent pathogen.

Inducible clindamycin resistance in Staphylococcus aureus isolates recovered from Mashhad, Iran.

BACKGROUND AND OBJECTIVES: Staphylococcus aureus is an important agent in hospital and community-associated infections, causing high morbidity and mortality. Introduction of the new antimicrobial classes for this pathogen has been usually followed by the emergence of resistant strains through multiple mechanisms. For instance, resistance to clindamycin (CLI)can be constitutive or inducible. Inducible clindamycin resistance which may lead to treatment failure can simply be identified by performing D-test. The aim of this study was to determine the prevalence of inducible clindamycin resistance among Staphylococcus aureus isolates by D-test method. MATERIALS AND METHODS: This was a cross-sectional study conducted on 211 non-duplicated S. aureus isolates in Imam Reza hospital of Mashhad during 2010. Susceptibility to oxacillin, cefoxitin, erythromycin and clindamycin was performed by agar disk diffusion method according to CLSI guidelines and D-shaped clindamycin susceptibility patterns where considered as D-test positive (D(+)). RESULTS: Of 211 S. aureus isolates,88 (41.7%) were methicillin resistant. It was found that of 88 MRSA isolates, 78 (88.6%) were erythromycin (ERY) resistant and 46 (52.3%) were CLI resistant. ERY and CLI resistance in MSSA strains was 22% and 10.6% respectively. Inducible clindamycin resistance was detected in 18 (20.5%) MRSA isolates. 47(53.4%) of MRSA isolates and 9 (7.3%) of MSSA showed constitutive MLS(B) phenotype. CONCLUSION: In conclusion, we found a high prevalence of inducible clindamycin resistance phenotype in our region. We recommend that whenever clindamycin is intended to be used for S. aureus infections, D-test should be performed to facilitate the appropriate treatment of patients.

Fabrication and mechanical properties of Al2O3/SiC/ZrO2 functionally graded material by electrophoretic deposition.

This study describes the synthesis of Al(2)O(3)/SiC/ZrO(2) functionally graded material (FGM) in bio-implants (artificial joints) by electrophoretic deposition (EPD). A suitable suspension that was based on 2-butanone was applied for the EPD of Al(2)O(3)/SiC/ZrO(2), and a pressureless sintering process was applied as a presintering. Hot isostatic pressing (HIP) was used to densify the deposit, with beneficial mechanical properties after 2 h at 1800 °C in Ar atmosphere. The maximum hardness in the outer layer (90 vol.% Al(2)O(3)+10 vol.% SiC) and maximum fracture toughness in the core layer (75 vol.% Al(2)O(3)+10 vol.% SiC + 15 vol.% ZrO(2)) composite were 20.8±0.3 GPa and 8±0.1 MPa m(1/2), respectively. The results, when compared with results from Al(2)O(3)/ZrO(2) FGM, showed that SiC increased the compressive stresses in the outer layers, while the inner layers were under a residual tensile stress.

Tools for developing a workplace violence prevention program.

This chapter details the efforts of a labor education program to develop a guidebook to provide unions and joint labor-management groups with tools that can be used to assess the risk of violence. The guidebook's hazard assessment checklist and policy checklist are reprinted at the end of the chapter.

Human immunodeficiency virus/acquired immunodeficiency syndrome training from a union perspective.

The authors developed a union sponsored 2-day human immunodeficiency virus/acquired immunodeficiency syndrome (HIV/AIDS) "train the trainer" program for healthcare workers in the San Francisco Bay Area. The program incorporated the "education for action" approach in an effort to respond to the inadequacies in many traditional, institutional trainings. Service Employees International Union (SEIU) and Labor Occupational Health Program (LOHP) conducted the HIV/AIDS "train the trainer" program for approximately 100 healthcare workers in county public hospitals and community health clinics. After completing the program, these workers went back to their healthcare facilities, or community organizations, and led additional classes on HIV/AIDS transmission and prevention for approximately 600 more people. The goal of the program was to empower healthcare workers to: 1) identify the occupational risks associated with exposure to blood and potentially infectious body fluids at the workplace; 2) develop strategies to reduce those risks; 3) discuss their feelings about caring for an HIV/AIDS patient; and, 4) conduct HIV/AIDS workshops at the workplace.

Molecular phylogeny of date palm (Phoenix dactylifera L.) cultivars from Saudi Arabia by DNA fingerprinting.

Genetic diversity among 13 different cultivars of date palm (Phoenix dactylifera L.) of Saudi Arabia was studied using random amplified polymorphic DNA (RAPD) markers. The screening of 140 RAPD primers allowed selection of 37 primers which revealed polymorphism, and the results were reproducible. All 13 genotypes were distinguishable by their unique banding patterns produced by 37 selected primers. Cluster analysis by the unweighted paired group method of arithmetic mean (UPGMA) showed two main clusters. Cluster A consisted of five cultivars (Shehel, Om-Kobar, Ajwa, Om-Hammam and Bareem) with 0.59-0.89 Nei and Li's coefficient in the similarity matrix. Cluster B consisted of seven cultivars (Rabeeha, Shishi, Nabtet Saif, Sugai, Sukkary Asfar, Sukkary Hamra and Nabtet Sultan) with a 0.66-0.85 Nei and Li's similarity range. Om-Hammam and Bareem were the two most closely related cultivars among the 13 cultivars with the highest value in the similarity matrix for Nei and Li's coefficient (0.89). Ajwa was closely related with Om-Hammam and Bareem with the second highest value in the similarity matrix (0.86). Sukkary Hamra and Nabtet Sultan were also closely related, with the third highest value in the similarity matrix (0.85). The cultivar Barny did not belong to any of the cluster groups. It was 34% genetically similar to the rest of the 12 cultivars. The average similarity among the 13 cultivars was more than 50%. As expected, most of the cultivars have a narrow genetic base. The results of the analysis can be used for the selection of possible parents to generate a mapping population. The variation detected among the closely related genotypes indicates the efficiency of RAPD markers over the morphological and isozyme markers for the identification and construction of genetic linkage maps.

Innate immune response of the human host to exposure with herpes simplex virus type 1: in vitro control of the virus infection by enhanced natural killer activity via interleukin-15 induction.

Infections with herpes simplex virus type 1 (HSV-1) in humans and in animal models are accompanied by enhanced natural killer (NK) activity. In vitro, HSV-1 also enhances the NK activity of human peripheral blood mononuclear cells (PBMC). The molecular basis of this enhanced NK activity, however, is not well characterized. We investigated the role of human interleukin-15 (IL-15) in this phenomenon and report here that HSV-1-mediated enhanced NK activity was abrogated by neutralizing antibodies for IL-15 but not for other cytokines (i.e., IL-2, IL-12, gamma interferon [IFN-gamma], tumor necrosis factor alpha, or IFN-alpha). Anti-CD122 antibodies which block signaling through IL-2 receptor beta chain, and therefore neutralize the effects of IL-15 (and IL-2), also abrogated this enhancement. Furthermore, HSV-1 increased the levels of IL-15 mRNA and the production of IL-15 in HSV-1-infected PBMC cultures. The neutralization of IL-15 in cocultures of PBMC with HSV-1-infected cells significantly increased HSV-1 production. These results strongly suggest a role for IL-15 in the HSV-1-mediated in vitro enhancement of NK activity and in the PBMC-mediated suppression of HSV-1 replication.

Up-regulation of NK cytotoxic activity via IL-15 induction by different viruses: a comparative study.

IL-15 is a recently identified cytokine that belongs to the four alpha-helix bundle cytokine family and possesses biological activities similar to those of IL-2. Its ability to induce effectors of NK activity suggests its involvement in innate immunity. In this study, we analyzed the effect of different viruses (HSV, EBV, respiratory syncitial virus, vesicular stomatitis virus, influenza virus, reovirus, and Sendai virus) on the up-regulation of NK activity in vitro. Exposure of human PBMC to the these viruses resulted in an immediate up-regulation of NK activity of PBMC via IL-15 induction; this effect was abrogated in the presence of mAbs to IL-15. Results of experiments conducted in parallel using mAbs to IL-15, as well as to other cytokines (IL-2, IL-12, IFN-gamma, and TNF-alpha), clearly indicated that IL-15 was specifically responsible for the observed effect. Furthermore, supernatants of virus-infected PBMC cultures significantly enhanced NK activity of uninfected PBMC in vitro. An increase of IL-15 protein levels 20 h postinfection was also confirmed in a bioassay using the IL-2-dependent cell line CTLL. Kinetic analysis of IL-15 mRNA expression using a semiquantitative RT-PCR revealed that the level of IL-15 messages peaked at different time points (up to 12 h) postinfection, depending on the nature of the virus. Taken together, these results suggest that the IL-15 response of the host to viral infection and the subsequent NK cell activation represent an important effector mechanism of the innate immune surveillance of the host against viral infections.

Direct cleavage of the human DNA fragmentation factor-45 by granzyme B induces caspase-activated DNase release and DNA fragmentation.

The protease granzyme B (GrB) plays a key role in the cytocidal activity during cytotoxic T lymphocyte (CTL)-mediated programmed cell death. Multiple caspases have been identified as direct substrates for GrB, suggesting that the activation of caspases constitutes an important event during CTL-induced cell death. However, recent studies have provided evidence for caspase-independent pathway(s) during CTL-mediated apoptosis. In this study, we demonstrate caspase-independent and direct cleavage of the 45 kDa unit of DNA fragmentation factor (DFF45) by GrB both in vitro and in vivo. Using a novel and selective caspase-3 inhibitor, we show the ability of GrB to process DFF45 directly and mediate DNA fragmentation in the absence of caspase-3 activity. Furthermore, studies with DFF45 mutants reveal that both caspase-3 and GrB share a common cleavage site, which is necessary and sufficient to induce DNA fragmentation in target cells during apoptosis. Together, our data suggest that CTLs possess alternative mechanism(s) for inducing DNA fragmentation without the requirement for caspases.