Echinocandin Treatment of Pneumocystis Pneumonia in Rodent Models Depletes Cysts Leaving Trophic Burdens That Cannot Transmit the Infection

Fungi in the genus Pneumocystis cause pneumonia (PCP) in hosts with debilitated immune systems and are emerging as co-morbidity factors associated with chronic diseases such as COPD. Limited therapeutic choices and poor understanding of the life cycle are a result of the inability of these fungi to grow outside the mammalian lung. Within the alveolar lumen, Pneumocystis spp., appear to have a bi-phasic life cycle consisting of an asexual phase characterized by binary fission of trophic forms and a sexual cycle resulting in formation of cysts, but the life cycle stage that transmits the infection is not known. The cysts, but not the trophic forms, express β -1,3-D-glucan synthetase and contain abundant β -1,3-D-glucan. Here we show that therapeutic and prophylactic treatment of PCP with echinocandins, compounds which inhibit the synthesis of β -1,3-D-glucan, depleted cysts in rodent models of PCP, while sparing the trophic forms which remained in significant numbers. Survival was enhanced in the echincandin treated mice, likely due to the decreased β -1,3-D-glucan content in the lungs of treated mice and rats which coincided with reductions of cyst numbers, and dramatic remodeling of organism morphology. Strong evidence for the cyst as the agent of transmission was provided by the failure of anidulafungin-treated mice to transmit the infection. We show for the first time that withdrawal of anidulafungin treatment with continued immunosuppression permitted the repopulation of cyst forms. Treatment of PCP with an echinocandin alone will not likely result in eradication of infection and cessation of echinocandin treatment while the patient remains immunosuppressed could result in relapse. Importantly, the echinocandins provide novel and powerful chemical tools to probe the still poorly understood bi-phasic life cycle of this genus of fungal pathogens

Pneumocystis murina colonization in immunocompetent surfactant protein A deficient mice following environmental exposure

<p>Abstract</p> <p>Background</p> <p><it>Pneumocystis spp</it>. are opportunistic pathogens that cause pneumonia in immunocompromised humans and animals. <it>Pneumocystis </it>colonization has also been detected in immunocompetent hosts and may exacerbate other pulmonary diseases. Surfactant protein A (SP-A) is an innate host defense molecule and plays a role in the host response to <it>Pneumocystis</it>.</p> <p>Methods</p> <p>To analyze the role of SP-A in protecting the immunocompetent host from <it>Pneumocystis </it>colonization, the susceptibility of immunocompetent mice deficient in SP-A (KO) and wild-type (WT) mice to <it>P. murina </it>colonization was analyzed by reverse-transcriptase quantitative PCR (qPCR) and serum antibodies were measured by enzyme-linked immunosorbent assay (ELISA).</p> <p>Results</p> <p>Detection of <it>P. murina </it>specific serum antibodies in immunocompetent WT and KO mice indicated that the both strains of mice had been exposed to <it>P. murina </it>within the animal facility. However, P. <it>murina </it>mRNA was only detected by qPCR in the lungs of the KO mice. The incidence and level of the mRNA expression peaked at 8–10 weeks and declined to undetectable levels by 16–18 weeks. When the mice were immunosuppressed, <it>P. murina </it>cyst forms were also only detected in KO mice. <it>P. murina </it>mRNA was detected in <it>SCID </it>mice that had been exposed to KO mice, demonstrating that the immunocompetent KO mice are capable of transmitting the infection to immunodeficient mice. The pulmonary cellular response appeared to be responsible for the clearance of the colonization. More CD4+ and CD8+ T-cells were recovered from the lungs of immunocompetent KO mice than from WT mice, and the colonization in KO mice depleted CD4+ cells was not cleared.</p> <p>Conclusion</p> <p>These data support an important role for SP-A in protecting the immunocompetent host from <it>P. murina </it>colonization, and provide a model to study <it>Pneumocystis </it>colonization acquired via environmental exposure in humans. The results also illustrate the difficulties in keeping mice from exposure to <it>P. murina </it>even when housed under barrier conditions.</p

Radiolytic Effects on Fluoride Impurities in a U{sub 3}O{sub 8} Matrix

The safe handling and storage of radioactive materials require an understanding of the effects of radiolysis on those materials. Radiolysis may result in the production of gases (e.g., corrosives) or pressures that are deleterious to storage containers. A study has been performed to address these concerns as they relate to the radiolysis of residual fluoride compounds in uranium oxides

"Powerful Placebo": Ein Lehr-Lern-Konzept zu Placebo- und Noceboeffekten in der kompetenzorientierten Kommunikationsausbildung

Aim: Placebo and nocebo effects are based on expectations that are formed by how doctors communicate and can influence the efficacy of medical treatment. Given the implications for doctor-patient communication and the learning objectives listed in NKLM 2.0, we herein present a novel teaching and learning concept to impart competency-based knowledge about placebo and nocebo effects. Method: The teaching and learning concept was piloted with N=324 third-semester medical students. It combines a self-guided, small-group component to gather communication strategies and apply them in a video-recorded conversation, followed by a classroom-based session to reflect on and discuss the videos and to learn basic scientific and theoretical knowledge. The evaluation involved written feedback from the students and lecturers (structure/process) and an analysis of the videos (students' learning success). To supplement this, the overall course evaluation was included since this new teaching concept was not specifically evaluated by the students.Results: Course structure and process were rated positively. The active involvement of the students in the subject matter and the balance between theoretical, scientific and practical content was emphasized positively. Analysis of the learning success showed that the students were able to effectively transfer the knowledge gained about placebo and nocebo effects to conversational situations.Conclusion: The topic of placebo/nocebo is optimally suited to teach communication skills with its many links to knowledge, translational approaches and added value for medical practice. When doing this, video-recorded conversations appear to be an effective tool to achieve learning objectives. This teaching and learning strategy offers possibilities for expanding communication curricula.Zielsetzung: Placebo- und Noceboeffekte basieren auf Erwartungen, die durch ärztliche Kommunikation geprägt werden und die Wirksamkeit medizinischer Behandlungen beeinflussen. Angesichts der Implikationen für die ärztliche Gesprächsführung und der im NKLM 2.0 hinterlegten Lernziele wurde ein Lehr-/Lernkonzept entwickelt und evaluiert, das kompetenzorientiert Wissen zu Placebo- und Noceboeffekten vermittelt.Methodik: Das Lehr-/Lernkonzept wurde bei N=324 Studierende im 3. Fachsemester Medizin erprobt. Es kombiniert eine Selbstlerneinheit in Kleingruppen zur Erarbeitung von Kommunikationsstrategien und deren Anwendung in einer videodokumentierten Gesprächssituation, sowie eine Präsenzeinheit zur Reflektion und Diskussion der Videos und zur Vermittlung wissenschaftlicher Grundlagen. Die Evaluation umfasste schriftliche Rückmeldungen der Lehrenden (Struktur/Prozess) sowie eine Analyse der Videodokumentation (Lernerfolg der Studierenden). Ergänzend wurde die Evaluation des Gesamtkurses herangezogen, da keine gezielte Evaluation des neuen Lehrkonzepts durch Studierende erfolgte. Ergebnisse: Struktur und Prozess des Kurses wurden seitens der Lehrenden als gut bewertet. Es wurden die aktive Auseinandersetzung der Studierenden mit der Thematik sowie die Balance zwischen theoretischen, wissenschaftlichen und praktischen Inhalten positiv hervorgehoben. Die Lernerfolgsanalyse zeigte, dass die Studierenden erworbenes Wissen zu Placebo- und Noceboeffekten erfolgreich auf Gesprächssituationen übertragen konnten.Schlussfolgerung: Mit vielfältigen Möglichkeiten zur Wissensverknüpfung, translationalen Ansätzen und Mehrwert für die ärztliche Praxis eignet sich das Thema Placebo/Nocebo optimal für die Vermittlung kommunikativer Kompetenzen. Ein wirksames Instrument zur Erreichung der Lernziele scheinen dabei die videodokumentierten Gesprächssituationen zu bieten. Das Lehr-/Lernkonzept bietet Anregungen zur Erweiterung von Kommunikationscurricula

Hydrofluoric Acid Corrosion Testing on Unplated and Electroless Gold-Plated Samples

The Molten Salt Reactor Experiment (MSRE) remediation requires that almost 40 kg of uranium hexafluoride (UF6) be converted to uranium oxide (UO). In the process of this conversion, six moles of hydrofluoric acid (HP) are produced for each mole of UF6 converted

Performance modeling of concrete/metal barriers used in low-level waste disposal

Low-Level radioactive wastes generated in government and commercial operations involving nuclear materials need to be isolated from the environment almost in perpetuity. An increasing number of disposal sites are using concrete/metal barriers (so called ``engineered`` barriers) to isolate these wastes from the environment. Two major concerns hamper the use of engineered barriers; namely, the lack of ability to reliably predict the service life of these barriers and to estimate the confidence level of the service life predicted. Computer codes (SOURCE1 and SOURCE2) for estimating the long-term (centuries to millennia) service life of these barriers are presented. These codes use mathematical models (based on past observations, currently accepted data, and established theories) to predict behavior into the future. Processes modeled for concrete degradation include sulfate attack, calcium hydroxide leaching, and reinforcement corrosion. The loss of structural integrity due to cracking is also modeled. Mechanisms modeled for nuclide leaching include advection and diffusion. The coupled or linked effects of these models are addressed in the codes. Outputs from the codes are presented and analyzed

Brain functional connectivity is associated with visceral sensitivity in women with Irritable Bowel Syndrome

Increased perception of visceral stimuli is a key feature of Irritable Bowel Syndrome (IBS). While altered resting-state functional connectivity (rsFC) has been also reported in IBS, the relationship between visceral hypersensitivity and aberrant rsFC is unknown. We therefore assessed rsFC within the salience, sensorimotor and default mode networks in patients with and without visceral hypersensitivity and in healthy controls (HCs).An exploratory resting-state functional magnetic resonance imaging study was performed in 41 women with IBS and 20 HCs. Group independent component analysis was used to derive intrinsic brain networks. Rectal thresholds were determined and patients were subdivided into groups with increased (hypersensitive IBS, N=21) or normal (normosensitive IBS, N=20) visceral sensitivity. Between-group comparisons of rsFC were carried-out using region-of-interest analyses and peak rsFC values were extracted for correlational analyses.Relative to normosensitive IBS, hypersensitive patients showed increased positive rsFC of pregenual anterior cingulate cortex and thalamus within the salience network and of posterior insula within the sensorimotor network. When compared to both hypersensitive IBS and HCs, normosensitive IBS showed decreased positive rsFC of amygdala and decreased negative rsFC in dorsal anterior insula within the DMN. DMN and sensorimotor network rsFC were associated with rectal perception thresholds, and rsFC in posterior insula was correlated with reported symptom severity in IBS.Our exploratory findings suggest that visceral sensitivity in IBS is related to changes in FC within resting-state networks associated with interoception, salience and sensory processing. These alterations may play an important role in hypervigilance and hyperalgesia in IBS. Keywords: Resting-state fMRI, Visceral hypersensitivity, Irritable Bowel Syndrome, Functional connectivity, Default mode network, Salience network, Sensorimotor networ