Ineffective hepatic clearance of excess ammonia in the form of urea, as occurs in urea cycle enzymopathies (UCDs) and in liver failure, leads to increases in circulating and tissue concentrations of ...glutamine and a positive correlation between brain glutamine and the severity of neurological symptoms. Studies using 1H/13C Nuclear Magnetic Resonance (NMR) spectroscopy reveal increased de novo synthesis of glutamine in the brain in acute liver failure (ALF) but increases of synthesis rates per se do not correlate with either the severity of encephalopathy or brain edema. Skeletal muscle becomes primarily responsible for removal of excess ammonia in liver failure and in UCDs, an adaptation that results from a post-translational induction of the glutamine synthetase (GS) gene. The importance of muscle in ammonia removal in hyperammonemia accounts for the resurgence of interest in maintaining adequate dietary protein and the use of agents aimed at the stimulation of muscle GS. Alternative or additional metabolic and regulatory pathways that impact on brain glutamine homeostasis in hyperammonemia include (i) glutamine deamination by the two isoforms of glutaminase, (ii) glutamine transamination leading to the production of the putative neurotoxin alpha-ketoglutaramate and (iii) alterations of high affinity astrocytic glutamine transporters (SNATs). Findings of reduced expression of the glutamine transporter SNAT-5 (responsible for glutamine clearance from the astrocyte) in ALF raise the possibility of “glutamine trapping” within these cells. Such a trapping mechanism could contribute to cytotoxic brain edema and to the imbalance between excitatory and inhibitory neurotransmission in this disorder.
We extend the semiclassical optimized mean trajectory (OMT) procedure to calculate electronic spectra for a dimer with excitonic and vibronic interactions. The electronic part of the quantum ...Hamiltonian is expressed in the Miller–Meyer–Stock–Thoss form with one fictitious harmonic oscillator per electronic state, and the classical limit is taken, transforming a quantum Hamiltonian governing discrete states to an equivalent classical form. The ad hoc addition of classical nuclear degrees of freedom and electron–nuclear coupling yields a classical Hamiltonian with one degree of freedom per each electronic state and also per each nuclear motion. Semiclassical quantization is applied to this Hamiltonian through the OMT, originally developed to describe nuclear dynamics on a single potential surface and subsequently generalized to include electronic transitions. The accuracy and practicality of this trajectory-based method is assessed for an excitonically coupled dimer. The semiclassical one- and two-dimensional spectra are shown to compare well with quantum dynamical calculations performed with the hierarchical equations of motion method.
Medical students as future clinicians will apply their anatomy knowledge in medical imaging. There are various radiological resources available for the medical students to learn anatomy and ...contextualise it to the clinical setting. Ultrasound is a safe and non- invasive imaging procedure commonly used in clinical practice. This study aimed to use portable ultrasound and evaluate its impact as an adjunct to cadaveric anatomy teaching together with cross sectional anatomy images and line diagrams.
Ultrasound teaching was incorporated into upper limb and lower limb anatomy practical dissecting room sessions. The number of medical students who participated was 121 students from the year 2008 - 2009 and 94 students from the year 2009- 2010. The students were divided into groups of 15-20. Initially ultrasound demonstration was carried out on a volunteer and then the students were given the opportunity to use the ultrasound and identify normal anatomical structures visualized on images. For the students in the year 2009- 2010, ultrasound teaching was supplemented with cross sectional anatomy images and line diagrams. Questionnaires were distributed with seven questions rated using four point Likert scale and free text. Qualitative data was analysed using 2- proportion Z test and Fischer's exact test.
The number of students in the 2009-2010 year group who were confident in interpreting ultrasound images increased significantly when compared to the 2008-2009 year group of students. The majority of students were able to identify structures like bone, muscles and blood vessels on ultrasound images. There was a significant increase in the number of students who found the ultrasound teaching useful and also those who regarded ultrasound to have improved understanding of anatomy considerably.
Ultrasound acts as a useful adjunct to teach anatomy in a clinical context to medical students. The use of cross sectional anatomy images and line diagrams together can aid ultrasound image orientation of structures during these sessions. Early exposure to this imaging technology may prime students for later encounters with ultrasound during clinical practice.
Two-dimensional electronic-vibrational (2DEV) spectra have the capacity to probe electron-nuclear interactions in molecules by measuring correlations between initial electronic excitations and ...vibrational transitions at a later time. The trajectory-based semiclassical optimized mean trajectory approach is applied to compute 2DEV spectra for a system with excitonically coupled electronic excited states vibronically coupled to a chromophore vibration. The chromophore mode is in turn coupled to a bath, inducing redistribution of vibrational populations. The lineshapes and delay-time dynamics of the resulting spectra compare well with benchmark calculations, both at the level of the observable and with respect to contributions from distinct spectroscopic processes.
NADPH is the reducing agent for mitochondrial H2O2 detoxification systems. Nicotinamide nucleotide transhydrogenase (NNT), an integral protein located in the inner mitochondrial membrane, contributes ...to an elevated mitochondrial NADPH/NADP+ ratio. This enzyme catalyzes the reduction of NADP+ at the expense of NADH oxidation and H+ reentry to the mitochondrial matrix. A spontaneous Nnt mutation in C57BL/6J (B6J-NntMUT) mice arose nearly 3 decades ago but was only discovered in 2005. Here, we characterize the consequences of the Nnt mutation on the mitochondrial redox functions of B6J-NntMUT mice. Liver mitochondria were isolated both from an Nnt wild-type C57BL/6 substrain (B6JUnib-NntW) and from B6J-NntMUT mice. The functional evaluation of respiring mitochondria revealed major redox alterations in B6J-NntMUT mice, including an absence of transhydrogenation between NAD and NADP, higher rates of H2O2 release, the spontaneous oxidation of NADPH, the poor ability to metabolize organic peroxide, and a higher susceptibility to undergo Ca2+-induced mitochondrial permeability transition. In addition, the mitochondria of B6J-NntMUT mice exhibited increased oxidized/reduced glutathione ratios as compared to B6JUnib-NntW mice. Nonetheless, the maximal activity of NADP-dependent isocitrate dehydrogenase, which is a coexisting source of mitochondrial NADPH, was similar between both groups. Altogether, our data suggest that NNT functions as a high-capacity source of mitochondrial NADPH and that its functional loss due to the Nnt mutation results in mitochondrial redox abnormalities, most notably a poor ability to sustain NADP and glutathione in their reduced states. In light of these alterations, the potential drawbacks of using B6J-NntMUT mice in biomedical research should not be overlooked.
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•The NNT enzyme is a source of NADPH in the mitochondrial matrix.•C57BL/6J mice strain lacks NNT activity due to a Nnt gene mutation.•C57BL/6J mitochondria are unable to properly metabolize exogenous peroxide.•Intact mitochondria from C57BL/6J mice exhibit several redox abnormalities.•The widespread use of C57BL/6J mice in biomedical research should be reassessed.
Neuropathologic investigations in acute liver failure (ALF) reveal significant alterations to neuroglia consisting of swelling of astrocytes leading to cytotoxic brain edema and intracranial ...hypertension as well as activation of microglia indicative of a central neuroinflammatory response. Increased arterial ammonia concentrations in patients with ALF are predictors of patients at risk for the development of brain herniation. Molecular and spectroscopic techniques in ALF reveal alterations in expression of an array of genes coding for neuroglial proteins involved in cell volume regulation and mitochondrial function as well as in the transport of neurotransmitter amino acids and in the synthesis of pro-inflammatory cytokines. Liver-brain pro-inflammatory signaling mechanisms involving transduction of systemically-derived cytokines, ammonia neurotoxicity and exposure to increased brain lactate have been proposed. Mild hypothermia and N-Acetyl cysteine have both hepato-protective and neuro-protective properties in ALF. Potentially effective anti-inflammatory agents aimed at control of encephalopathy and brain edema in ALF include etanercept and the antibiotic minocycline, a potent inhibitor of microglial activation. Translation of these potentially-interesting findings to the clinic is anxiously awaited.
The present systematic review with meta-analysis was undertaken to review the evidence base in support of a beneficial effect of L-ornithine L-aspartate (LOLA) for the prevention/prophylaxis of overt ...hepatic encephalopathy (OHE) in patients with cirrhosis. Using appropriate keywords and electronic and manual searches together with established inclusion/exclusion criteria, six randomized controlled trials (RCTs) for a total of 384 patients were identified five of which were of high quality and low risk of bias according to Jadad-Cochrane criteria. Treatment with LOLA resulted in significant reductions in the risk of progression to OHE in MHE patients (3 studies) with RR: 0.23 95% CI: 0.07, 0.73,
p
< 0.01. LOLA was also effective for secondary OHE prophylaxis with RR: 0.389 95% CI: 0.174–0.870
p
< 0.002 as well as for primary prophylaxis for OHE following acute variceal bleeding RR: 0.42 95% CI: 0.16–0.98
p
< 0.03 and for OHE prophylaxis post-TIPSS RR: 0.30 95% CI: 0.03–2.66 compared to placebo/no intervention in all cases. OHE prevention/prophylaxis was accompanied by significant reductions of blood ammonia. Both oral and intravenous formulations of LOLA appeared to be effective for the prevention of progression to OHE in patients with MHE. These findings provide the first direct evidence of potential benefit of LOLA for the prevention of OHE in cirrhosis across a range of clinical presentations.
For clinical research findings to improve the quality of care and outcomes for newborn infants and their families, they need to be implemented in policy and adopted in practice.
We describe the ...principles of effective dissemination and implementation of research findings and highlight examples of collaborative quality improvement strategies to ensure that guidelines, protocols, policies and practices reflect research-informed evidence.
Passive dissemination of research findings is generally ineffective in driving change. Implementation strategies that use multi-faceted approaches acting on different barriers to change are better at driving improvements in the quality of care practices. These initiatives are increasingly embedded within regional, national and international networks of neonatal care centres that collaborate in conducting research, implementing its findings and auditing its uptake. Examples of successful network-based collaborative quality improvement programmes include efforts to increase use of evidence-based strategies to prevent hospital-acquired bloodstream infections, optimise surfactant replacement for preterm infants, reduce the incidence of bronchopulmonary dysplasia, improve antibiotic stewardship and promote the use of human milk to prevent necrotising enterocolitis in very-low-birth-weight infants.
Effective dissemination and implementation are essential for research evidence to improve quality of care and outcomes for newborn infants and their families. Multifaceted initiatives within network-based collaborative quality improvement programmes facilitate continuous audit and benchmarking cycles to ensure equity of access to evidence-based care practices.
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