Festival Choir, D.F. Cook, conductor (December 1, 1991)

Festival Choir, D.F. Cook, conductor (December 1, 1991

Systems Toxicology Approach to Identifying Paracetamol Overdose

Paracetamol (acetaminophen (APAP)) is one of the most commonly used analgesics in the United Kingdom and the United States. However, exceeding the maximum recommended dose can cause serious liver injury and even death. Promising APAP toxicity biomarkers are thought to add value to those used currently and clarification of the functional relationships between these biomarkers and liver injury would aid clinical implementation of an improved APAP toxicity identification framework. The framework currently used to define an APAP overdose is highly dependent upon time since ingestion and initial dose; information that is often highly unpredictable. A pharmacokinetic/pharmacodynamic (PK/PD) APAP model has been built in order to understand the relationships between a panel of biomarkers and APAP dose. Visualization and statistical tools have been used to predict initial APAP dose and time since administration. Additionally, logistic regression analysis has been applied to histology data to provide a prediction of the probability of liver injury

Total Hip Prostheses in Standing, Sitting and Squatting Positions: An Overview of Our 8 Years Practice Using the EOS Imaging Technology

This is an open access article licensed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/3.0/) which permits unrestricted, non-commercial use, distribution and reproduction in any medium, provided the work is properly cited.More total hip arthroplasty (THA) is performed worldwide and especially in younger and more active patients compared to earlier decades. One of the focuses of THA research in the future will be on optimizing the radiological follow-up of these patients using 2D and 3D measurements of implants position while reducing the radiation dose delivered. Low-dose EOS(®) imaging is an innovative slot-scanning radiograph system providing valuable information in patient functional positions (standing, sitting and even squatting positions). EOS has been proven accurate and reliable without significant inconvenience caused by the metallic artifacts of implants. The ability to obtain precise data on implant orientation according to the patient posture opens new perspectives for a comprehensive analysis of the pelvic frontal and sagittal balance and its potential impact on implants function and failures. We report our 8 years experience on our first 300 THA patients using this technology routinely for pre and post op evaluation. Our results will be compared and confronted with the actual literature about this innovative technology. We shall especially emphasize our experience about patients with abnormal posture and the evolution of the subject over time, because the phenomenon of an aging spine is frequently associated with the process of aging hips

Secreted HMGB1 from Wnt activated intestinal cells is required to maintain a crypt progenitor phenotype

BACKGROUND AND AIMS: Colorectal cancer (CRC) arises via multiple genetic changes. Mutation of the tumour suppressor gene APC, a key regulator of Wnt signalling, is recognised as a frequent early driving mutation in CRC. We have previously shown that conditional loss of Apc within the murine small intestine (Apcfloxmice) results in acute Wnt signalling activation, altered crypt-villus architecture and many hallmarks of neoplasia. Our transctipomic profiling (Affymetrix Microarrays) and proteomic profiling (iTRAQ-QSTAR) of Apc-deficient intestine inferred the involvement of High Mobility Group Box 1 (Hmgb1) in CRC pathogenesis. Here we assess the contribution of HMGB1 to the crypt progenitor phenotype seen following Apc loss. RESULTS: Elevated HMGB1 was confirmed in intestinal epithelia and serum following conditional loss of Apc. Treatment of Apcflox mice with anti-HMGB1 neutralising antibody significantly reduced many of the crypt progenitor phenotypes associated with Apc loss; proliferation and apoptosis levels were reduced, cell differentiation was restored and the expansion of stem cell marker expression was eradicated. METHODS: Hmgb1 levels in intestinal epithelia and serum in Apcflox and ApcMin mice were assessed using qRT-PCR, Western blot and ELISA assays. The functional importance of elevated extracellular Hmgb1 was assessed using an anti-HMGB1 neutralising antibody in Apcflox mice. CONCLUSIONS: HMGB1 is expressed and secreted from intestinal epithelial cells in response to Wnt signalling activation. This secreted HMGB1 is required to maintain nearly all aspects of the crypt progenitor phenotype observed following Apc loss and add to the body of accumulating evidence indicating that targeting HMGB1 may be a viable novel therapeutic approach

Social Determinants of Health Are Associated with Markers of Renal Injury in Adolescents with Type 1 Diabetes.

OBJECTIVE: To examine the relationship between the social determinants of health and markers of early renal injury in adolescent patients with type 1 diabetes (T1D). STUDY DESIGN: Renal outcomes included estimated glomerular filtration rate (eGFR) and albumin-creatinine excretion ratio (ACR). Differences in urinary and serum inflammatory markers also were assessed in relation to social determinants of health. Regression analysis was used to evaluate the association between the Ontario Marginalization Index (ON-Marg) as a measure of the social determinants of health, patient characteristics, ACR, eGFR, and renal filtration status (hyperfiltration vs normofiltration). RESULTS: Participants with T1D (n = 199) with a mean age of 14.4 ± 1.7 years and diabetes duration of 7.2 ± 3.1 years were studied. Mean eGFR was 122.0 ± 19.4 mL/min/1.73 m2. Increasing marginalization was positively associated with eGFR (P < .0001) but not with ACR (P = .605). Greater marginalization was associated with greater median levels of urinary interleukin (IL)-2, IL-12 (p40), macrophage-derived chemokine, monocyte chemoattractant protein-3, and tumor necrosis factor-β and serum IL-2. ON-Marg was significantly associated with eGFR after we controlled for age, sex, body mass index z score, ethnicity, serum glucose, and hemoglobin A1c in linear regression. A similar association between hyperfiltration and ON-Marg score was observed in multivariable logistic regression. CONCLUSION: Increasing marginalization is significantly associated with both eGFR and hyperfiltration in adolescents with T1D and is associated with significant changes in urinary inflammatory biomarkers. These findings highlight a potentially important interaction between social and biological determinants of health in adolescents with T1D

Overscreened multi-channel SU(N) Kondo model : large-N solution and Conformal Field Theory

The multichannel Kondo model with SU(N) spin symmetry and SU(K) channel symmetry is considered. The impurity spin is chosen to transform as an antisymmetric representation of SU(N), corresponding to a fixed number of Abrikosov fermions $\sum_{\alpha}f_{\alpha}^{\dagger}f_{\alpha}=Q$. For more than one channel (K>1), and all values of N and Q, the model displays non-Fermi behaviour associated with the overscreening of the impurity spin. Universal low-temperature thermodynamic and transport properties of this non-Fermi liquid state are computed using conformal field theory methods. A large-N limit of the model is then considered, in which K/N and Q/N are held fixed. Spectral densities satisfy coupled integral equations in this limit, corresponding to a (time-dependent) saddle-point. A low frequency, low-temperature analysis of these equations reveals universal scaling properties in the variable $\omega/T$, also predicted from conformal invariance. The universal scaling form is obtained analytically and used to compute the low-temperature universal properties of the model in the large-N limit, such as the T=0 residual entropy and residual resistivity, and the critical exponents associated with the specific heat and susceptibility. The connections with the ``non-crossing approximation'' and the previous work of Cox and Ruckenstein are discussed.Comment: 39 pages, RevTeX, including 5 figures in encapsulated postscript forma

Louis de La Forge and the ‘Non-Transfer Argument’ for Occasionalism

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The GZK cutoff behind a Magnetized Universe

We study the effect of random extra-galactic magnetic fields on the propagation of protons of energy larger than $10^{19}$ eV. We show that for reasonable field values (in the 100 nG range) the transition between diffusive and ballistic regimes occurs in the same energy range as the GZK cutoff (a few $10^{19}$ eV). The usual interpretation of the flux reduction above the GZK energy in terms of a sudden reduction of the visible horizon is modified. Moreover, since the size of the diffusion sphere of a continuous source of cosmic rays is of the order of 10 Mpc, the local structure of the Universe and therefore of potential local astrophysical sources plays a dominant role in the expected spectrum. Under reasonable assumptions on the sources configurations the expected GZK cutoff is reduced

Impact of dietary fiber on gut microbiota composition, function and gut-brain-modules in healthy adults – a systematic review protocol [version 2; peer review: 2 approved]

Background The gut microbiota has been extensively implicated in health and disease. The functional outputs of the gut microbiota, such as microbial metabolites, are considered particularly important in this regard. Significant associations exist between alterations in the relative abundance of specific microbial taxa and mental health disorders. Dietary fiber has the potential to alter gut microbiota composition and function, modifying bacterial enzymatic function and the production of metabolites. As many taxa of microorganisms have enzymes capable of producing or degrading neurochemicals i.e. neuroactive gut brain modules, new predictive tools can be applied to existing datasets such as those harvested from dietary fiber interventions. We endeavor to perform a systematic review in order to identify studies reporting compositional gut microbiota alterations after interventions with dietary fiber in healthy individuals. We aim to also extract from the selected studies publicly available microbial genomic sequence datasets for reanalysis with a consistent bioinformatics pipeline, with the ultimate intention of identifying altered gut brain modules following dietary fiber interventions. Methods Interventional trials and randomized controlled studies that are originally published, including cross-over and non-crossover design and involving healthy adult humans will be included. A systematic search of PubMed/MEDLINE and EMBASE, two electronic databases, will be completed. Discussion Various types of dietary fiber have an impact on the gut microbiota composition, with some promoting the growth of particular taxa while others are reduced in relative abundance. Our search focuses on the impact of this food component on the microbiota of healthy individuals. Compositional gut microbial changes have been reported and our review will compile and update these observations after reanalysis of their datasets with a consistent bioinformatic pipeline. From this it may be possible to predict more detailed functional consequences in terms of neuroactive gut brain modules, of the compositional alterations in gut microbial taxa