Triheptanoin: A Rescue Therapy for Cardiogenic Shock in Carnitine-acylcarnitine Translocase Deficiency.

Carnitine-acylcarnitine translocase (CACT) deficiency is a rare long-chain fatty acid oxidation disorder (LC-FAOD) with high mortality due to cardiomyopathy or lethal arrhythmia. Triheptanoin (UX007), an investigational drug composed of synthetic medium odd-chain triglycerides, is a novel therapy in development for LC-FAOD patients. However, cases of its safe and efficacious use to reverse severe heart failure in CACT deficiency are limited. Here, we present a detailed report of an infant with CACT deficiency admitted in metabolic crisis that progressed into severe cardiogenic shock who was successfully treated by triheptanoin. The child was managed, thereafter, on triheptanoin until her death at 3 years of age from a cardiopulmonary arrest in the setting of acute respiratory illness superimposed on chronic hypercarbic respiratory failure

Enzymology of the branched-chain amino acid oxidation disorders: the valine pathway

Valine is one of the three branched-chain amino acids which undergoes oxidation within mitochondria. In this paper, we describe the current state of knowledge with respect to the enzymology of the valine oxidation pathway and the different disorders affecting oxidation

Herders and hazards: covariate dzud risk and the cost of risk management strategies in a Mongolian subdistrict

Studies of mobile pastoralist livelihoods have shown that a variety of sociotechnical practices have been developed to achieve reliable outputs from livestock in variable arid and semi-arid environments. This paper builds upon the concept of pastoralists as high-reliability seekers rather than risk-averse and makes a case for understanding Mongolian herders as well adapted to livestock production in highly variable climatic conditions within a certain threshold of risk and uncertainty. This system fails, however, during instances of high uncertainty and covariate risk such as in cases of the natural hazard dzud, which requires individual households to make significant cash investments in risk management. It forwards the idea that investing in local government—soum and bag level— administrative capacity and infrastructure is needed to build system resilience to covariate risk. Based on ethnographic research in rural Bayankhongor, this paper interrogates how dzud interfaces with socio-economic factors amongst pastoralists in central west Mongolia

Effectiveness of a smartphone app in increasing physical activity amongst male adults: a randomised controlled trial.

BACKGROUND: Smartphones are ideal for promoting physical activity in those with little intrinsic motivation for exercise. This study tested three hypotheses: H1 - receipt of social feedback generates higher step-counts than receipt of no feedback; H2 - receipt of social feedback generates higher step-counts than only receiving feedback on one's own walking; H3 - receipt of feedback on one's own walking generates higher step-counts than no feedback (H3). METHODS: A parallel group randomised controlled trial measured the impact of feedback on steps-counts. Healthy male participants (n = 165) aged 18-40 were given phones pre-installed with an app that recorded steps continuously, without the need for user activation. Participants carried these with them as their main phones for a two-week run-in and six-week trial. Randomisation was to three groups: no feedback (control); personal feedback on step-counts; group feedback comparing step-counts against those taken by others in their group. The primary outcome measure, steps per day, was assessed using longitudinal multilevel regression analysis. Control variables included attitude to physical activity and perceived barriers to physical activity. RESULTS: Fifty-five participants were allocated to each group; 152 completed the study and were included in the analysis: n = 49, no feedback; n = 53, individual feedback; n = 50, individual and social feedback. The study provided support for H1 and H3 but not H2. Receipt of either form of feedback explained 7.7 % of between-subject variability in step-count (F = 6.626, p < 0.0005). Compared to the control, the expected step-count for the individual feedback group was 60 % higher (effect on log step-count = 0.474, 95 % CI = 0.166-0.782) and that for the social feedback group, 69 % higher (effect on log step-count = 0.526, 95 % CI = 0.212-0.840). The difference between the two feedback groups (individual vs social feedback) was not statistically significant. CONCLUSIONS: Always-on smartphone apps that provide step-counts can increase physical activity in young to early-middle-aged men but the provision of social feedback has no apparent incremental impact. This approach may be particularly suitable for inactive people with low levels of physical activity; it should now be tested with this population

Choice of Bacterial Growth Medium Alters the Transcriptome and Phenotype of Salmonella enterica Serovar Typhimurium

The type of bacterial culture medium is an important consideration during design of any experimental protocol. The aim of this study was to understand the impact of medium choice on bacterial gene expression and physiology by comparing the transcriptome of Salmonella enterica SL1344 after growth in the widely used LB broth or the rationally designed MOPS minimal medium. Transcriptomics showed that after growth in MOPS minimal media, compared to LB, there was increased expression of 42 genes involved in amino acid synthesis and 23 genes coding for ABC transporters. Seven flagellar genes had decreased expression after growth in MOPS minimal medium and this correlated with a decreased motility. In both MOPS minimal medium and MEM expression of genes from SPI-2 was increased and the adhesion of S. Typhimurium to intestinal epithelial cells was higher compared to the levels after growth in LB. However, SL1344 invasion was not significantly altered by growth in either MOPs minimal media or MEM. Expression of SPI-2 was also measured using chromosomal GFP reporter fusions followed by flow cytometry which showed, for the first time, that the reduction in SPI-2 transcript after growth in different media related to a reduction in the proportion of the bacterial population expressing SPI-2. These data highlight the profound differences in the global transcriptome after in vitro growth in different media and show that choice of medium should be considered carefully during experimental design, particularly when virulence related phenotypes are being measured

Women convicted for violent offenses: Adverse childhood experiences, low level of education and poor mental health

<p>Abstract</p> <p>Background</p> <p>In past years, the female offender population has grown, leading to an increased interest in the characteristics of female offenders. The aim of this study was to assess the prevalence of female violent offending in a Swiss offender population and to compare possible socio-demographic and offense-related gender differences.</p> <p>Methods</p> <p>Descriptive and bivariate logistic regression analyses were performed for a representative sample of N = 203 violent offenders convicted in Zurich, Switzerland.</p> <p>Results</p> <p>7.9% (N = 16) of the sample were female. Significant gender differences were found: Female offenders were more likely to be married, less educated, to have suffered from adverse childhood experiences and to be in poor mental health. Female violent offending was less heterogeneous than male violent offending, in fact there were only three types of violent offenses females were convicted for in our sample: One third were convicted of murder, one third for arson and only one woman was convicted of a sex offense.</p> <p>Conclusions</p> <p>The results of our study point toward a gender-specific theory of female offending, as well as toward the importance of developing models for explaining female criminal behavior, which need to be implemented in treatment plans and intervention strategies regarding female offenders.</p

The Host Range of Gammaretroviruses and Gammaretroviral Vectors Includes Post-Mitotic Neural Cells

Gammaretroviruses and gammaretroviral vectors, in contrast to lentiviruses and lentiviral vectors, are reported to be restricted in their ability to infect growth-arrested cells. The block to this restriction has never been clearly defined. The original assessment of the inability of gammaretroviruses and gammaretroviral vectors to infect growth-arrested cells was carried out using established cell lines that had been growth-arrested by chemical means, and has been generalized to neurons, which are post-mitotic. We re-examined the capability of gammaretroviruses and their derived vectors to efficiently infect terminally differentiated neuroendocrine cells and primary cortical neurons, a target of both experimental and therapeutic interest.Using GFP expression as a marker for infection, we determined that both growth-arrested (NGF-differentiated) rat pheochromocytoma cells (PC12 cells) and primary rat cortical neurons could be efficiently transduced, and maintained long-term protein expression, after exposure to murine leukemia virus (MLV) and MLV-based retroviral vectors. Terminally differentiated PC12 cells transduced with a gammaretroviral vector encoding the anti-apoptotic protein Bcl-xL were protected from cell death induced by withdrawal of nerve growth factor (NGF), demonstrating gammaretroviral vector-mediated delivery and expression of genes at levels sufficient for therapeutic effect in non-dividing cells. Post-mitotic rat cortical neurons were also shown to be susceptible to transduction by murine replication-competent gammaretroviruses and gammaretroviral vectors.These findings suggest that the host range of gammaretroviruses includes post-mitotic and other growth-arrested cells in mammals, and have implications for re-direction of gammaretroviral gene therapy to neurological disease

MPA in Labor: Securing the Pearl Cays of Nicaragua

Implementation of Marine Protected Areas (MPAs) has always a step-zero, i.e., an initial phase when the idea is incepted, communicated and negotiated among stakeholders. What happens during this phase is likely to have an impact later on. If not done right, the management of the MPA may encounter problems at later stage that will be difficult to correct. Inspired by this working theory, this article describes the effort to establish the Pearl Cays off the Caribbean coast of Nicaragua as a protected area. This case-study illustrates the critical actions to be taken during step-zero, i.e., what needs to be considered and done before an MPA is formally declared. The area investigated consists of a number of small islands (cays) and coral reefs, fishing grounds and marine turtle nesting areas. Throughout history, the cays have played an important role in sustaining livelihoods of nearby communities. Although the idea of an MPA was originally conservation, the communities saw it as an opportunity to regain ownership and control of the cays. By Nicaraguan law, in order to establish protected areas, consultation and approval from local people is required. In the case of the Pearl Cays, this has proved difficult. The article demonstrates how MPA initiatives must sometimes relate to already ongoing complex social processes in the area where they are to be instigated

Dynamic simulations on the mitochondrial fatty acid Beta-oxidation network

<p>Abstract</p> <p>Background</p> <p>The oxidation of fatty acids in mitochondria plays an important role in energy metabolism and genetic disorders of this pathway may cause metabolic diseases. Enzyme deficiencies can block the metabolism at defined reactions in the mitochondrion and lead to accumulation of specific substrates causing severe clinical manifestations. Ten of the disorders directly affecting mitochondrial fatty acid oxidation have been well-defined, implicating episodic hypoketotic hypoglycemia provoked by catabolic stress, multiple organ failure, muscle weakness, or hypertrophic cardiomyopathy. Additionally, syndromes of severe maternal illness (HELLP syndrome and AFLP) have been associated with pregnancies carrying a fetus affected by fatty acid oxidation deficiencies. However, little is known about fatty acids kinetics, especially during fasting or exercise when the demand for fatty acid oxidation is increased (catabolic stress).</p> <p>Results</p> <p>A computational kinetic network of 64 reactions with 91 compounds and 301 parameters was constructed to study dynamic properties of mitochondrial fatty acid β-oxidation. Various deficiencies of acyl-CoA dehydrogenase were simulated and verified with measured concentrations of indicative metabolites of screened newborns in Middle Europe and South Australia. The simulated accumulation of specific acyl-CoAs according to the investigated enzyme deficiencies are in agreement with experimental data and findings in literature. Investigation of the dynamic properties of the fatty acid β-oxidation reveals that the formation of acetyl-CoA – substrate for energy production – is highly impaired within the first hours of fasting corresponding to the rapid progress to coma within 1–2 hours. LCAD deficiency exhibits the highest accumulation of fatty acids along with marked increase of these substrates during catabolic stress and the lowest production rate of acetyl-CoA. These findings might confirm gestational loss to be the explanation that no human cases of LCAD deficiency have been described.</p> <p>Conclusion</p> <p>In summary, this work provides a detailed kinetic model of mitochondrial metabolism with specific focus on fatty acid β-oxidation to simulate and predict the dynamic response of that metabolic network in the context of human disease. Our findings offer insight into the disease process (e.g. rapid progress to coma) and might confirm new explanations (no human cases of LCAD deficiency), which can hardly be obtained from experimental data alone.</p

Jet energy measurement with the ATLAS detector in proton-proton collisions at root s=7 TeV

The jet energy scale and its systematic uncertainty are determined for jets measured with the ATLAS detector at the LHC in proton-proton collision data at a centre-of-mass energy of √s = 7TeV corresponding to an integrated luminosity of 38 pb-1. Jets are reconstructed with the anti-kt algorithm with distance parameters R=0. 4 or R=0. 6. Jet energy and angle corrections are determined from Monte Carlo simulations to calibrate jets with transverse momenta pT≥20 GeV and pseudorapidities {pipe}η{pipe}<4. 5. The jet energy systematic uncertainty is estimated using the single isolated hadron response measured in situ and in test-beams, exploiting the transverse momentum balance between central and forward jets in events with dijet topologies and studying systematic variations in Monte Carlo simulations. The jet energy uncertainty is less than 2. 5 % in the central calorimeter region ({pipe}η{pipe}<0. 8) for jets with 60≤pT<800 GeV, and is maximally 14 % for pT<30 GeV in the most forward region 3. 2≤{pipe}η{pipe}<4. 5. The jet energy is validated for jet transverse momenta up to 1 TeV to the level of a few percent using several in situ techniques by comparing a well-known reference such as the recoiling photon pT, the sum of the transverse momenta of tracks associated to the jet, or a system of low-pT jets recoiling against a high-pT jet. More sophisticated jet calibration schemes are presented based on calorimeter cell energy density weighting or hadronic properties of jets, aiming for an improved jet energy resolution and a reduced flavour dependence of the jet response. The systematic uncertainty of the jet energy determined from a combination of in situ techniques is consistent with the one derived from single hadron response measurements over a wide kinematic range. The nominal corrections and uncertainties are derived for isolated jets in an inclusive sample of high-pT jets. Special cases such as event topologies with close-by jets, or selections of samples with an enhanced content of jets originating from light quarks, heavy quarks or gluons are also discussed and the corresponding uncertainties are determined. © 2013 CERN for the benefit of the ATLAS collaboration