Idiopathic pancreatitis is a consequence of an altering spectrum of bile nucleation time

<p>Abstract</p> <p>Background</p> <p>The pathogenesis of idiopathic pancreatitis (IP) remains poorly understood. Our hypothesis is that IP is a sequel of micro-crystallization of hepatic bile.</p> <p>Methods</p> <p>A prospective case control study compared 55 patients; symptomatic cholelithiasis - 30 (14 male, median age 36 years; mean BMI - 25.1 kg/m²), gallstone pancreatitis - 9 (3 male, median age 35 years; mean BMI - 24.86 kg/m²) and IP - 16 (9 male, median age 34 years; mean BMI -23.34 kg/m²) with 30 controls (15 male, median age 38 years; mean BMI = 24.5 kg/m²) undergoing laparotomy for conditions not related to the gall bladder and bile duct. Ultrafiltered bile from the common hepatic duct in patients and controls was incubated in anaerobic conditions and examined by polarized light microscopy to assess bile nucleation time (NT). In the analysis, the mean NT of patients with gallstones and gallstone pancreatitis was taken as a cumulative mean NT for those with established gallstone disease (EGD).</p> <p>Results</p> <p>Patients were similar to controls. Mean NT in all groups of patients was significantly shorter than controls (EGD cumulative mean NT, 1.73 +/- 0.2 days vs. controls, 12.74 +/- 0.4 days, P = 0.001 and IP patients mean NT, 3.1 +/- 0.24 days vs. controls, 12.74 +/- 0.4 days, P = 0.001). However, NT in those with IP was longer compared with those with EGD (mean NT in IP, 3.1 +/- 0.24 days vs. cumulative mean in EGD: 1.73 +/- 0.2 days, P = 0.002).</p> <p>Conclusion</p> <p>Nucleation time of bile in patients with IP is abnormal and is intermediate to nucleation time of lithogenic bile at one end of the spectrum of lithogenicity and non-lithogenic bile, at the other end.</p

Optima TB: A tool to help optimally allocate tuberculosis spending.

Approximately 85% of tuberculosis (TB) related deaths occur in low- and middle-income countries where health resources are scarce. Effective priority setting is required to maximise the impact of limited budgets. The Optima TB tool has been developed to support analytical capacity and inform evidence-based priority setting processes for TB health benefits package design. This paper outlines the Optima TB framework and how it was applied in Belarus, an upper-middle income country in Eastern Europe with a relatively high burden of TB. Optima TB is a population-based disease transmission model, with programmatic cost functions and an optimisation algorithm. Modelled populations include age-differentiated general populations and higher-risk populations such as people living with HIV. Populations and prospective interventions are defined in consultation with local stakeholders. In partnership with the latter, demographic, epidemiological, programmatic, as well as cost and spending data for these populations and interventions are then collated. An optimisation analysis of TB spending was conducted in Belarus, using program objectives and constraints defined in collaboration with local stakeholders, which included experts, decision makers, funders and organisations involved in service delivery, support and technical assistance. These analyses show that it is possible to improve health impact by redistributing current TB spending in Belarus. Specifically, shifting funding from inpatient- to outpatient-focused care models, and from mass screening to active case finding strategies, could reduce TB prevalence and mortality by up to 45% and 50%, respectively, by 2035. In addition, an optimised allocation of TB spending could lead to a reduction in drug-resistant TB infections by 40% over this period. This would support progress towards national TB targets without additional financial resources. The case study in Belarus demonstrates how reallocations of spending across existing and new interventions could have a substantial impact on TB outcomes. This highlights the potential for Optima TB and similar modelling tools to support evidence-based priority setting

The Escherichia coli SOS Gene dinF Protects against Oxidative Stress and Bile Salts

DNA is constantly damaged by physical and chemical factors, including reactive oxygen species (ROS), such as superoxide radical (O2−), hydrogen peroxide (H2O2) and hydroxyl radical (•OH). Specific mechanisms to protect and repair DNA lesions produced by ROS have been developed in living beings. In Escherichia coli the SOS system, an inducible response activated to rescue cells from severe DNA damage, is a network that regulates the expression of more than 40 genes in response to this damage, many of them playing important roles in DNA damage tolerance mechanisms. Although the function of most of these genes has been elucidated, the activity of some others, such as dinF, remains unknown. The DinF deduced polypeptide sequence shows a high homology with membrane proteins of the multidrug and toxic compound extrusion (MATE) family. We describe here that expression of dinF protects against bile salts, probably by decreasing the effects of ROS, which is consistent with the observed decrease in H2O2-killing and protein carbonylation. These results, together with its ability to decrease the level of intracellular ROS, suggests that DinF can detoxify, either direct or indirectly, oxidizing molecules that can damage DNA and proteins from both the bacterial metabolism and the environment. Although the exact mechanism of DinF activity remains to be identified, we describe for the first time a role for dinF

A biophysical model of dynamic balancing of excitation and inhibition in fast oscillatory large-scale networks

Over long timescales, neuronal dynamics can be robust to quite large perturbations, such as changes in white matter connectivity and grey matter structure through processes including learning, aging, development and certain disease processes. One possible explanation is that robust dynamics are facilitated by homeostatic mechanisms that can dynamically rebalance brain networks. In this study, we simulate a cortical brain network using the Wilson-Cowan neural mass model with conduction delays and noise, and use inhibitory synaptic plasticity (ISP) to dynamically achieve a spatially local balance between excitation and inhibition. Using MEG data from 55 subjects we find that ISP enables us to simultaneously achieve high correlation with multiple measures of functional connectivity, including amplitude envelope correlation and phase locking. Further, we find that ISP successfully achieves local E/I balance, and can consistently predict the functional connectivity computed from real MEG data, for a much wider range of model parameters than is possible with a model without ISP

25th Annual Computational Neuroscience Meeting: CNS-2016

Abstracts of the 25th Annual Computational Neuroscience Meeting: CNS-2016 Seogwipo City, Jeju-do, South Korea. 2–7 July 201

26th Annual Computational Neuroscience Meeting (CNS*2017): Part 3 - Meeting Abstracts - Antwerp, Belgium. 15–20 July 2017

This work was produced as part of the activities of FAPESP Research,\ud Disseminations and Innovation Center for Neuromathematics (grant\ud 2013/07699-0, S. Paulo Research Foundation). NLK is supported by a\ud FAPESP postdoctoral fellowship (grant 2016/03855-5). ACR is partially\ud supported by a CNPq fellowship (grant 306251/2014-0)

25th annual computational neuroscience meeting: CNS-2016

The same neuron may play different functional roles in the neural circuits to which it belongs. For example, neurons in the Tritonia pedal ganglia may participate in variable phases of the swim motor rhythms [1]. While such neuronal functional variability is likely to play a major role the delivery of the functionality of neural systems, it is difficult to study it in most nervous systems. We work on the pyloric rhythm network of the crustacean stomatogastric ganglion (STG) [2]. Typically network models of the STG treat neurons of the same functional type as a single model neuron (e.g. PD neurons), assuming the same conductance parameters for these neurons and implying their synchronous firing [3, 4]. However, simultaneous recording of PD neurons shows differences between the timings of spikes of these neurons. This may indicate functional variability of these neurons. Here we modelled separately the two PD neurons of the STG in a multi-neuron model of the pyloric network. Our neuron models comply with known correlations between conductance parameters of ionic currents. Our results reproduce the experimental finding of increasing spike time distance between spikes originating from the two model PD neurons during their synchronised burst phase. The PD neuron with the larger calcium conductance generates its spikes before the other PD neuron. Larger potassium conductance values in the follower neuron imply longer delays between spikes, see Fig. 17.Neuromodulators change the conductance parameters of neurons and maintain the ratios of these parameters [5]. Our results show that such changes may shift the individual contribution of two PD neurons to the PD-phase of the pyloric rhythm altering their functionality within this rhythm. Our work paves the way towards an accessible experimental and computational framework for the analysis of the mechanisms and impact of functional variability of neurons within the neural circuits to which they belong