Development of a Model of Pediatric Lung Failure Pathophysiology

A pediatric artificial lung (PAL) is under development as a bridge to transplantation or lung remodeling for children with end-stage lung failure (ESLF). To evaluate the efficiency of a PAL, a disease model mimicking the physiologic derangements of pediatric ESLF is needed. Our previous right pulmonary artery (rPA) ligation model (rPA-LM) achieved that goal, but caused immediate mortality in nearly half of the animals. In this study, we evaluated a new technique of gradual postoperative right pulmonary artery occlusion using a Rummel tourniquet (rPA-RT) in seven (25–40 kg) sheep. This technique created a stable model of ESLF pathophysiology, characterized by high alveolar dead space (58.0% ± 3.8%), pulmonary hypertension (38.4 ± 2.2 mm Hg), tachypnea (79 ± 20 breaths per minute), and intermittent supplemental oxygen requirement. This improvement to our technique provides the necessary physiologic derangements for testing a PAL, whereas avoiding the problem of high immediate perioperative mortality

Magnetic field stabilization for high-accuracy mass measurements on exotic nuclides

The magnetic-field stability of a mass spectrometer plays a crucial role in precision mass measurements. In the case of mass determination of short-lived nuclides with a Penning trap, major causes of instabilities are temperature fluctuations in the vicinity of the trap and pressure fluctuations in the liquid helium cryostat of the superconducting magnet. Thus systems for the temperature and pressure stabilization of the Penning trap mass spectrometer ISOLTRAP at the ISOLDE facility at CERN have been installed. A reduction of the fluctuations by at least one order of magnitude downto dT=+/-5mK and dp=+/-50mtorr has been achieved, which corresponds to a relative frequency change of 2.7x10^{-9} and 1.5x10^{-10}, respectively. With this stabilization the frequency determination with the Penning trap only shows a linear temporal drift over several hours on the 10 ppb level due to the finite resistance of the superconducting magnet coils.Comment: 23 pages, 13 figure

Signals for a Transition from Surface to Bulk Emission in Thermal Multifragmentation

Excitation-energy-gated two-fragment correlation functions have been studied between 2 to 9A MeV of excitation energy for equilibrium-like sources formed in $\pi^-$ and p + $^{197}$Au reactions at beam momenta of 8,9.2 and 10.2 GeV/c. Comparison of the data to an N-body Coulomb-trajectory code shows a decrease of one order of magnitude in the fragment emission time in the excitation energy interval 2-5A MeV, followed by a nearly constant breakup time at higher excitation energy. The observed decrease in emission time is shown to be strongly correlated with the increase of the fragment emission probability, and the onset of thermally-induced radial expansion. This result is interpreted as evidence consistent with a transition from surface-dominated to bulk emission expected for spinodal decomposition.Comment: 11 pages including 3 postscript figures (1 color

Growth control of the eukaryote cell: a systems biology study in yeast.

BACKGROUND: Cell growth underlies many key cellular and developmental processes, yet a limited number of studies have been carried out on cell-growth regulation. Comprehensive studies at the transcriptional, proteomic and metabolic levels under defined controlled conditions are currently lacking. RESULTS: Metabolic control analysis is being exploited in a systems biology study of the eukaryotic cell. Using chemostat culture, we have measured the impact of changes in flux (growth rate) on the transcriptome, proteome, endometabolome and exometabolome of the yeast Saccharomyces cerevisiae. Each functional genomic level shows clear growth-rate-associated trends and discriminates between carbon-sufficient and carbon-limited conditions. Genes consistently and significantly upregulated with increasing growth rate are frequently essential and encode evolutionarily conserved proteins of known function that participate in many protein-protein interactions. In contrast, more unknown, and fewer essential, genes are downregulated with increasing growth rate; their protein products rarely interact with one another. A large proportion of yeast genes under positive growth-rate control share orthologs with other eukaryotes, including humans. Significantly, transcription of genes encoding components of the TOR complex (a major controller of eukaryotic cell growth) is not subject to growth-rate regulation. Moreover, integrative studies reveal the extent and importance of post-transcriptional control, patterns of control of metabolic fluxes at the level of enzyme synthesis, and the relevance of specific enzymatic reactions in the control of metabolic fluxes during cell growth. CONCLUSION: This work constitutes a first comprehensive systems biology study on growth-rate control in the eukaryotic cell. The results have direct implications for advanced studies on cell growth, in vivo regulation of metabolic fluxes for comprehensive metabolic engineering, and for the design of genome-scale systems biology models of the eukaryotic cell.RIGHTS : This article is licensed under the BioMed Central licence at http://www.biomedcentral.com/about/license which is similar to the 'Creative Commons Attribution Licence'. In brief you may : copy, distribute, and display the work; make derivative works; or make commercial use of the work - under the following conditions: the original author must be given credit; for any reuse or distribution, it must be made clear to others what the license terms of this work are

Histopathological Changes and Clinical Responses of Buruli Ulcer Plaque Lesions during Chemotherapy: A Role for Surgical Removal of Necrotic Tissue?

The tropical necrotizing skin disease Buruli ulcer (BU) caused by Mycobacterium ulcerans is associated with extensive tissue destruction and local immunosuppression caused by the macrolide exotoxin mycolactone. Chemotherapy with a combination of rifampicin and streptomycin for 8 weeks is the currently recommended treatment for all types of BU lesions, including both ulcerative and non-ulcerative stages (plaques, nodules and edema). Our histopathological analysis of twelve BU plaque lesions revealed extensive destruction of sub-cutaneous tissue. This frequently led to ulceration during antibiotic treatment. This should not be mistaken as a failure of the antimycobacterial chemotherapy, since we found no evidence for the persistence of active infection foci. Large necrotic areas were found to persist even after completion of antibiotic treatment. These may disturb wound healing and the role of wound debridement should therefore be formally tested in a clinical trial setting

Derrida's 'The Purveyor of Truth' and constitutional reading

In this article the author explores Jacques Derrida’s reading in ‘The Purveyor of Truth’ of Edgar Allan Poe’s ‘The Purloined Letter’. In his essay, Derrida proposes a reading which differs markedly from the interpretation proposed by Lacan in his Seminar on ‘The Purloined Letter’. To appreciate Derrida’s reading, which is not hermeneutic-semantic in nature like that of Lacan, it is necessary to look at the relation of Derrida’s essay to his other texts on psychoanalysis, more specifically insofar as the Freudian death drive is concerned. The present article explores this ‘notion’ as elaborated on by Freud in Beyond the Pleasure Principle as well as Derrida’s reading of this text. It also investigates the importance of the ‘notion’ of the death drive as well as the significance of Derrida’s reading of The Purloined Letter for constitutional interpretation

Factors associated with pre-ART loss-to-follow up in adults in rural KwaZulu-Natal, South Africa:a prospective cohort study

Background: Timely initiation of antiretroviral treatment (ART) requires sustained engagement in HIV care before treatment eligibility. We assessed loss to follow-up (LTFU) correlates in HIV-positive adults accessing HIV treatment and care, not yet ART-eligible (CD4 &gt;500 cells/mm3).Methods: This was a sub-study of a prospective cohort study (focusing on sexual behaviour) in an area of high HIV prevalence and widespread ART availability in rural KwaZulu-Natal, South Africa. Psychosocial, clinical and demographic data were collected at recruitment from individuals with CD4 &gt;500 cells/mm3. LTFU was defined as not attending clinic within 13 months of last visit or before death. Individuals starting ART were censored at ART initiation. Data were collected between January 2009 and January 2013. Analysis used Competing Risks regression.Results: Two hundred forty-seven individuals (212 females) were recruited (median follow-up 2.13 years, total follow-up 520.15 person-years). 86 remained in pre-ART care (34.8 %), 94 were LTFU (38.1 %), 58 initiated ART (23.5 %), 7 died (2.8 %), 2 transferred out (0.8 %). The LTFU rate was 18.07 per 100 person-years (95 % CI 14.76–21.12). LTFU before a competing event was 13.5 % at one and 34.4 % at three years. Lower LTFU rates were significantly associated with age (&gt;37 versus ?37 years: adjusted sub-Hazard ratio (aSHR) 0.51, 95 % CI 0.30–0.87), openness with family/friends (a little versus not at all, aSHR 0.81, 95 % CI 0.45–1.43; a lot versus not at all, aSHR 1.57, 95 % CI 0.94–2.62), children (0 versus 4+, aSHR 0.68, 95 % CI 0.24–1.87; 1 versus 4+, aSHR 2.05 95 % CI 1.14–3.69, 2 versus 4+; aSHR 1.71, 95 % CI 0.94–3.09; 3 versus 4a, aSHR 1.14, 95 % CI 0.57–2.30), previous CD4 counts (1 versus 0, aSHR 0.81, 95 % CI 0.45–1.43; 2+ versus 0, aSHR 0.43, 95 % CI 0.25–0.73), and most recent partner HIV status (not known versus HIV-positive, aSHR 0.77, 95 % CI 0.50–1.19; HIV-negative versus HIV-positive, aSHR 2.40, 95 % CI 1.18–4.88). The interaction between openness with family/friends and HIV partner disclosure was close to significance (p?=?0.06). Those who had neither disclosed to partners nor were open with family/friends had lowest LTFU rates.Conclusions: Strategies to retain younger people in pre-ART care are required. How openness with others, partner HIV status and disclosure, and children relate to LTFU needs further exploration.<br/

Membrane Association of the PTEN Tumor Suppressor: Molecular Details of the Protein-Membrane Complex from SPR Binding Studies and Neutron Reflection

The structure and function of the PTEN phosphatase is investigated by studying its membrane affinity and localization on in-plane fluid, thermally disordered synthetic membrane models. The membrane association of the protein depends strongly on membrane composition, where phosphatidylserine (PS) and phosphatidylinositol diphosphate (PI(4,5)P2) act pronouncedly synergistic in pulling the enzyme to the membrane surface. The equilibrium dissociation constants for the binding of wild type (wt) PTEN to PS and PI(4,5)P2 were determined to be Kd∼12 µM and 0.4 µM, respectively, and Kd∼50 nM if both lipids are present. Membrane affinities depend critically on membrane fluidity, which suggests multiple binding sites on the protein for PI(4,5)P2. The PTEN mutations C124S and H93R show binding affinities that deviate strongly from those measured for the wt protein. Both mutants bind PS more strongly than wt PTEN. While C124S PTEN has at least the same affinity to PI(4,5)P2 and an increased apparent affinity to PI(3,4,5)P3, due to its lack of catalytic activity, H93R PTEN shows a decreased affinity to PI(4,5)P2 and no synergy in its binding with PS and PI(4,5)P2. Neutron reflection measurements show that the PTEN phosphatase “scoots" along the membrane surface (penetration <5 Å) but binds the membrane tightly with its two major domains, the C2 and phosphatase domains, as suggested by the crystal structure. The regulatory C-terminal tail is most likely displaced from the membrane and organized on the far side of the protein, ∼60 Å away from the bilayer surface, in a rather compact structure. The combination of binding studies and neutron reflection allows us to distinguish between PTEN mutant proteins and ultimately may identify the structural features required for membrane binding and activation of PTEN