A Computational Model of Hepatic Energy Metabolism: Understanding Zonated Damage and Steatosis in NAFLD.

In non-alcoholic fatty liver disease (NAFLD), lipid build-up and the resulting damage is known to occur more severely in pericentral cells. Due to the complexity of studying individual regions of the sinusoid, the causes of this zone specificity and its implications on treatment are largely ignored. In this study, a computational model of liver glucose and lipid metabolism is presented which treats the sinusoid as the repeating unit of the liver rather than the single hepatocyte. This allows for inclusion of zonated enzyme expression by splitting the sinusoid into periportal to pericentral compartments. By simulating insulin resistance (IR) and high intake diets leading to the development of steatosis in the model, we identify key differences between periportal and pericentral cells accounting for higher susceptibility to pericentral steatosis. Secondly, variation between individuals is seen in both susceptibility to steatosis and in its development across the sinusoid. Around 25% of obese individuals do not show excess liver fat, whilst 16% of lean individuals develop NAFLD. Furthermore, whilst pericentral cells tend to show higher lipid levels, variation is seen in the predominant location of steatosis from pericentral to pan-sinusoidal or azonal. Sensitivity analysis was used to identify the processes which have the largest effect on both total hepatic triglyceride levels and on the sinusoidal location of steatosis. As is seen in vivo, steatosis occurs when simulating IR in the model, predominantly due to increased uptake, along with an increase in de novo lipogenesis. Additionally, concentrations of glucose intermediates including glycerol-3-phosphate increased when simulating IR due to inhibited glycogen synthesis. Several differences between zones contributed to a higher susceptibility to steatosis in pericentral cells in the model simulations. Firstly, the periportal zonation of both glycogen synthase and the oxidative phosphorylation enzymes meant that the build-up of glucose intermediates was less severe in the periportal hepatocyte compartments. Secondly, the periportal zonation of the enzymes mediating β-oxidation and oxidative phosphorylation resulted in excess fats being metabolised more rapidly in the periportal hepatocyte compartments. Finally, the pericentral expression of de novo lipogenesis contributed to pericentral steatosis when additionally simulating the increase in sterol-regulatory element binding protein 1c (SREBP-1c) seen in NAFLD patients in vivo. The hepatic triglyceride concentration was predicted to be most sensitive to inter-individual variation in the activity of enzymes which, either directly or indirectly, determine the rate of free fatty acid (FFA) oxidation. The concentration was most strongly dependent on the rate constants for β-oxidation and oxidative phosphorylation. It also showed moderate sensitivity to the rate constants for processes which alter the allosteric inhibition of β-oxidation by acetyl-CoA. The predominant sinusoidal location of steatosis meanwhile was most sensitive variations in the zonation of proteins mediating FFA uptake or triglyceride release as very low density lipoproteins (VLDL). Neither the total hepatic concentration nor the location of steatosis showed strong sensitivity to variations in the lipogenic rate constants

Dosimetry of 3 CBCT devices for oral and maxillofacial radiology: CB Mercuray, NewTom 3G and i-CAT

Cone beam computed tomography (CBCT), which provides a lower dose, lower cost alternative to conventional CT, is being used with increasing frequency in the practice of oral and maxillofacial radiology. This study provides comparative measurements of effective dose for three commercially available, large (12'') field-of-view (FOV), CBCT units: CB Mercuray, NewTom 3G and i-CAT. Thermoluminescent dosemeters (TLDs) were placed at 24 sites throughout the layers of the head and neck of a tissue-equivalent human skull RANDO phantom. Depending on availability, the 12'' FOV and smaller FOV scanning modes were used with similar phantom positioning geometry for each CBCT unit. Radiation weighted doses to individual organs were summed using 1990 (E(1990)) and proposed 2005 (E(2005 draft)) ICRP tissue weighting factors to calculate two measures of whole-body effective dose. Dose as a multiple of a representative panoramic radiography dose was also calculated. For repeated runs dosimetry was generally reproducible within 2.5%. Calculated doses in microSv [corrected] (E(1990), E(2005 draft)) were NewTom3G (45, 59), i-CAT (135, 193) and CB Mercuray (477, 558). These are 4 to 42 times greater than comparable panoramic examination doses (6.3 microSv [corrected] 13.3 mSv). Reductions in dose were seen with reduction in field size and mA and kV technique factors. CBCT dose varies substantially depending on the device, FOV and selected technique factors. Effective dose detriment is several to many times higher than conventional panoramic imaging and an order of magnitude or more less than reported doses for conventional CT

The concept of remembrance in Walter Benjamin

This thesis argues that the role played by the concept of remembrance (Eingedenken) in Walter Benjamin's 'theory of the knowledge of history' and in his engagement with Enlightenment universal history, is a crucial one. The implications of Benjamin's contention that history's 'original vocation' is 'remembrance' have hitherto gone largely unnoticed. The following thesis explores the meaning of the concept of remembrance and assesses the significance of this proposed link between history and memory, looking at both the mnemonic aspect of history and the historical facets of memory. It argues that by mobilising the simultaneously destructive and constructive capacities of remembrance, Benjamin sought to develop a critical historiography which would enable a radical encounter with a previously suppressed past. In so doing he takes up a stance (explicit and implicit) towards existing philosophical conceptions of history, in particular the idea of universal history found in German Idealism. Benjamin reveals an intention to retain the epistemological aspirations of universal history whilst ridding that approach of its apologetic moment. He criticises existing conceptions of history on the basis that each assumes homogeneous time to be the framework in which historical events occur. Insight into the distinctive temporality of remembrance proves to be the touchstone for this critique, and provides a paradigm for a very different conception of time. The thesis goes on to determine what is valid and what is problematic both in this concept of remembrance and in the theory of historical knowledge which it informs, by subjecting both to the most cogent criticisms which can be levelled at them. What emerges is not only the importance of this concept for an understanding of Benjamin's philosophy but the pertinence of this concept for any philosophical account of memory

Prevalence and Predictors of Vitamin D Insufficiency in Children: A Great Britain Population Based Study

Objectives To evaluate the prevalence and predictors of vitamin D insufficiency (VDI) in children In Great Britain. Design A nationally representative cross-sectional study survey of children (1102) aged 4–18 years (999 white, 570 male) living in private households (January 1997–1998). Interventions provided information about dietary habits, physical activity, socio-demographics, and blood sample. Outcome measures were vitamin D insufficiency (<50 nmol/L). Results Vitamin D levels (mean = 62.1 nmol/L, 95%CI 60.4–63.7) were insufficient in 35%, and decreased with age in both sexes (p<0.001). Young People living between 53–59 degrees latitude had lower levels (compared with 50–53 degrees, p = 0.045). Dietary intake and gender had no effect on vitamin D status. A logistic regression model showed increased risk of VDI in the following: adolescents (14–18 years old), odds ratio (OR) = 3.6 (95%CI 1.8–7.2) compared with younger children (4–8 years); non white children (OR = 37 [95%CI 15–90]); blood levels taken December-May (OR = 6.5 [95%CI 4.3–10.1]); on income support (OR = 2.2 [95%CI 1.3–3.9]); not taking vitamin D supplementation (OR = 3.7 [95%CI 1.4–9.8]); being overweight (OR 1.6 [95%CI 1.0–2.5]); <1/2 hour outdoor exercise/day/week (OR = 1.5 [95%CI 1.0–2.3]); watched >2.5 hours of TV/day/week (OR = 1.6[95%CI 1.0–2.4]). Conclusion We confirm a previously under-recognised risk of VDI in adolescents. The marked higher risk for VDI in non-white children suggests they should be targeted in any preventative strategies. The association of higher risk of VDI among children who exercised less outdoors, watched more TV and were overweight highlights potentially modifiable risk factors. Clearer guidelines and an increased awareness especially in adolescents are needed, as there are no recommendations for vitamin D supplementation in older children

Preliminary Limits on the WIMP-Nucleon Cross Section from the Cryogenic Dark Matter Search (CDMS)

We are conducting an experiment to search for WIMPs, or weakly-interacting massive particles, in the galactic halo using terrestrial detectors. This generic class of hypothetical particles, whose properties are similar to those predicted by extensions of the standard model of particle physics, could comprise the cold component of non-baryonic dark matter. We describe our experiment, which is based on cooled germanium and silicon detectors in a shielded low-background cryostat. The detectors achieve a high degree of background rejection through the simultaneous measurement of the energy in phonons and ionization. Using exposures on the order of one kilogram-day from initial runs of our experiment, we have achieved (preliminary) upper limits on the WIMP-nucleon cross section that are comparable to much longer runs of other experiments.Comment: 5 LaTex pages, 5 eps figs, epsf.sty, espcrc2dsa2.sty. Proceedings of TAUP97, Gran Sasso, Italy, 7-11 Sep 1997, Nucl. Phys. Suppl., A. Bottino, A. di Credico and P. Monacelli (eds.). See also http://cfpa.berkeley.ed

Celecoxib exerts protective effects in the vascular endothelium via COX-2-independent activation of AMPK-CREB-Nrf2 signalling

Although concern remains about the athero-thrombotic risk posed by cyclo-oxygenase (COX)-2-selective inhibitors, recent data implicates rofecoxib, while celecoxib appears equivalent to NSAIDs naproxen and ibuprofen. We investigated the hypothesis that celecoxib activates AMP kinase (AMPK) signalling to enhance vascular endothelial protection. In human arterial and venous endothelial cells (EC), and in contrast to ibuprofen and naproxen, celecoxib induced the protective protein heme oxygenase-1 (HO-1). Celecoxib derivative 2,5-dimethyl-celecoxib (DMC) which lacks COX-2 inhibition also upregulated HO-1, implicating a COX-2-independent mechanism. Celecoxib activated AMPKα(Thr172) and CREB-1(Ser133) phosphorylation leading to Nrf2 nuclear translocation. Importantly, these responses were not reproduced by ibuprofen or naproxen, while AMPKα silencing abrogated celecoxib-mediated CREB and Nrf2 activation. Moreover, celecoxib induced H-ferritin via the same pathway, and increased HO-1 and H-ferritin in the aortic endothelium of mice fed celecoxib (1000 ppm) or control chow. Functionally, celecoxib inhibited TNF-α-induced NF-κB p65(Ser536) phosphorylation by activating AMPK. This attenuated VCAM-1 upregulation via induction of HO-1, a response reproduced by DMC but not ibuprofen or naproxen. Similarly, celecoxib prevented IL-1β-mediated induction of IL-6. Celecoxib enhances vascular protection via AMPK-CREB-Nrf2 signalling, a mechanism which may mitigate cardiovascular risk in patients prescribed celecoxib. Understanding NSAID heterogeneity and COX-2-independent signalling will ultimately lead to safer anti-inflammatory drugs

Healthcare quality improvement and ‘work engagement’; concluding results from a national, longitudinal, cross-sectional study of the ‘Productive Ward-Releasing Time to Care’ programme

Concerns about patient safety and reducing harm have led to a particular focus on initiatives that improve healthcare quality. However Quality Improvement (QI) initiatives have in the past typically faltered because they fail to fully engage healthcare professionals, resulting in apathy and resistance amongst this group of key stakeholders. Productive Ward: Releasing Time to Care (PW) is a ward-based QI programme created to help ward-based teams redesign and streamline the way that they work; leaving more time to care for patients. PW is designed to engage and empower ward-based teams to improve the safety, quality and delivery of care

Stress induced polarization of immune-neuroendocrine phenotypes in Gallus gallus

Immune-neuroendocrine phenotypes (INPs) stand for population subgroups differing in immune-neuroendocrine interactions. While mammalian INPs have been characterized thoroughly in rats and humans, avian INPs were only recently described in Coturnix coturnix (quail). To assess the scope of this biological phenomenon, herein we characterized INPs in Gallus gallus (a domestic hen strain submitted to a very long history of strong selective breeding pressure) and evaluated whether a social chronic stress challenge modulates the individuals’ interplay affecting the INP subsets and distribution. Evaluating plasmatic basal corticosterone, interferon-γ and interleukin-4 concentrations, innate/acquired leukocyte ratio, PHA-P skin-swelling and induced antibody responses, two opposite INP profiles were found: LEWIS-like (15% of the population) and FISCHER-like (16%) hens. After chronic stress, an increment of about 12% in each polarized INP frequency was found at expenses of a reduction in the number of birds with intermediate responses. Results show that polarized INPs are also a phenomenon occurring in hens. The observed inter-individual variation suggest that, even after a considerable selection process, the population is still well prepared to deal with a variety of immune-neuroendocrine challenges. Stress promoted disruptive effects, leading to a more balanced INPs distribution, which represents a new substrate for challenging situations.Fil: Nazar, Franco Nicolas. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba. Instituto de Investigaciones Biológicas y Tecnológicas. Universidad Nacional de Córdoba. Facultad de Ciencias Exactas, Físicas y Naturales. Instituto de Investigaciones Biológicas y Tecnológicas; ArgentinaFil: Estevez, Inma. Centro de Investigación. Neiker - Tecnalia; EspañaFil: Correa, Silvia Graciela. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Córdoba. Centro de Investigaciones en Bioquímica Clínica e Inmunología; ArgentinaFil: Marin, Raul Hector. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba. Instituto de Investigaciones Biológicas y Tecnológicas. Universidad Nacional de Córdoba. Facultad de Ciencias Exactas, Físicas y Naturales. Instituto de Investigaciones Biológicas y Tecnológicas; Argentin

cAMP-Signalling Regulates Gametocyte-Infected Erythrocyte Deformability Required for Malaria Parasite Transmission.

Blocking Plasmodium falciparum transmission to mosquitoes has been designated a strategic objective in the global agenda of malaria elimination. Transmission is ensured by gametocyte-infected erythrocytes (GIE) that sequester in the bone marrow and at maturation are released into peripheral blood from where they are taken up during a mosquito blood meal. Release into the blood circulation is accompanied by an increase in GIE deformability that allows them to pass through the spleen. Here, we used a microsphere matrix to mimic splenic filtration and investigated the role of cAMP-signalling in regulating GIE deformability. We demonstrated that mature GIE deformability is dependent on reduced cAMP-signalling and on increased phosphodiesterase expression in stage V gametocytes, and that parasite cAMP-dependent kinase activity contributes to the stiffness of immature gametocytes. Importantly, pharmacological agents that raise cAMP levels in transmissible stage V gametocytes render them less deformable and hence less likely to circulate through the spleen. Therefore, phosphodiesterase inhibitors that raise cAMP levels in P. falciparum infected erythrocytes, such as sildenafil, represent new candidate drugs to block transmission of malaria parasites

Occupational Therapy for South Asian Older Adults in the United Kingdom: Cross-Cultural Issues

Introduction There is limited understanding of the cultural needs of diverse Black and Minority Ethnic populations such as South Asian older adults, which may be perpetuating occupational injustices and health inequalities faced by these groups. Although cultural considerations are intrinsic to person-centred occupational therapy and increasingly relevant to the changing landscape of health and social care, the profession is criticised for its western-centric focus. This study aimed to gain understanding of the current cross-cultural issues in supporting South Asian older adults in the UK, as perceived by occupational therapists. Method A constructivist qualitative design supported by thematic analysis was used, involving seven occupational therapists in the United Kingdom who participated in semi-structured interviews via Skype/telephone. Findings Cross-cultural issues were illustrated through the following themes: ‘when the barriers go down’ – cultural mismatch in individualist vs. collectivist worldviews; ‘invasion of the family home’ – cultural inappropriateness of standard interventions; and ‘I go into every assessment assuming nothing’ – recognition of and response to challenges. Conclusion This study provides insight into cross-cultural issues in occupational therapy for South Asian older adults, revealing a gap between theory and practice in integrating cultural humility. It highlights the need for a more inclusive, person-centred approach to support culturally diverse populations