Inhibitory feedback control of NF-κB signalling in health and disease.

Cells must adapt to changes in their environment to maintain cell, tissue and organismal integrity in the face of mechanical, chemical or microbiological stress. Nuclear factor-κB (NF-κB) is one of the most important transcription factors that controls inducible gene expression as cells attempt to restore homeostasis. It plays critical roles in the immune system, from acute inflammation to the development of secondary lymphoid organs, and also has roles in cell survival, proliferation and differentiation. Given its role in such critical processes, NF-κB signalling must be subject to strict spatiotemporal control to ensure measured and context-specific cellular responses. Indeed, deregulation of NF-κB signalling can result in debilitating and even lethal inflammation and also underpins some forms of cancer. In this review, we describe the homeostatic feedback mechanisms that limit and 're-set' inducible activation of NF-κB. We first describe the key components of the signalling pathways leading to activation of NF-κB, including the prominent role of protein phosphorylation and protein ubiquitylation, before briefly introducing the key features of feedback control mechanisms. We then describe the array of negative feedback loops targeting different components of the NF-κB signalling cascade including controls at the receptor level, post-receptor signalosome complexes, direct regulation of the critical 'inhibitor of κB kinases' (IKKs) and inhibitory feedforward regulation of NF-κB-dependent transcriptional responses. We also review post-transcriptional feedback controls affecting RNA stability and translation. Finally, we describe the deregulation of these feedback controls in human disease and consider how feedback may be a challenge to the efficacy of inhibitors

Pharmacodynamic differentiation of lorazepam sleepiness and dizziness using an ordered categorical measure

Categorical measures of lorazepam sleepiness and dizziness were modeled to identify differences in pharmacodynamic (PD) parameters between these adverse events (AEs). Differences in data-derived PD parameters were compared with relative incidence rates in the drug label (15.7% and 6.9%, respectively). Healthy volunteers ( n  = 20) received single oral doses of 2 mg lorazepam or placebo in a randomized, double-blind, cross-over fashion. A seven-point categorical scale measuring the intensity of AEs was serially administered over 24 h. The maximum score (MaxS), and area under the effect curve (AUEC) were determined by noncompartmental methods and compared using a paired t -test. Individual scores were modeled using a logistic function implemented in NONMEM. AUEC and MaxS for sleepiness were significantly higher than dizziness (20.35 vs. 9.76, p  < 0.01) and (2.35 vs. 1.45, p  < 0.01). Model slope estimates were similar for sleepiness and dizziness (0.21 logits × mL/ng vs. 0.19 logits × mL/ng), but baseline logits were significantly higher for sleepiness (−2.81 vs. −4.34 logits). Data-derived PD parameters were in concordance with label incidence rates. The higher intensity of sleepiness may be directly related to baseline (no drug present) while the increase in intensity as a result of drug was relatively similar for both AEs. © 2010 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 99:3628–3641, 2010Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/77428/1/22093_ftp.pd

Kinetics, dynamics, and bioavailability of bumetanide in healthy subjects and patients with congestive heart failure

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/110076/1/cptclpt1988186.pd

A service improvement ‘tool kit’ for effective heart failure management in primary care

Background: Heart failure (HF) is a complex and highly debilitating clinical syndrome. International guidelines identify the optimum clinical management of patients living with HF in primary care but translation of these into practice remains inadequate. The aim of this service evaluation is to measure standards of HF diagnosis and management, before and after the implementation of The Greater Manchester Heart Failure Investigation Tool (GM-HFIT), a facilitated ‘tool kit’ designed to optimise HF care. Methods: The GM-HFIT was developed as a means of assessing and improving care and was implemented as part of a facilitated service improvement and evaluation in primary care using a prospective, pre-test, post-test design. Results: Anonymised pre- and post-audit data were taken from a sample of 1130 cases entered on general practice HF registers. These cases were from two clinical commissioning groups (39 general practices) in the north west of England and were analysed to compare HF management and treatment parameters against clinical guidelines. Implementation of the GM-HFIT tool kit was associated with a reduction in the number of patients inappropriately placed on the HF register (p<0.001), an improvement in the recording and documentation of pulse rate and rhythm (p=0.005) and the proportion of patients receiving the target dose of angiotensin converting enzyme inhibitors and beta-blockers (p<0.001). There was no significant difference in the recording and documentation of blood pressure levels or in documented target blood pressure levels across the time points. Conclusion: The introduction of the GM-HFIT kit was associated with statistically significant improvements in the identification and clinical management of patients diagnosed with HF in primary care

Discriminative and aversive properties of [beta]-carboline-3-carboxylic acid ethyl ester, a benzodiazepine receptor inverse agonist, in rhesus monkey

Rhesus monkeys were trained to discriminate injections of saline from those of [beta]-carboline-3-carboxylic acid ethyl ester ([beta]-CCE), a compound that binds to the benzodiazepine receptor, but often has actions opposite to those of the benzodiazepines. A benzodiazepine agonist midazolam and low doses of a specific benzodiazepine antagonist, Ro 15-1788, reversed the discriminative effects of [beta]-CCE. Higher doses of Ro 15-1788 produced stimulus effects similar to [beta]-CCE. In a separate experiment, monkeys responded to terminate intravenous infusions of [beta]-CCE, but not midazolam. This aversive effect of [beta]-CCE was reversed by Ro 15-1788. The behavioral effects of [beta]-CCE in these non-human primates are consistent with other data that have shown it to act on benzodiazepine receptors, and support the hypothesis that [beta]-CCE can be considered an inverse agonist at this receptor.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/26229/1/0000309.pd

Temporal and spatial perspectives on the fate of anthropogenic carbon : a carbon cycle slide deck for broad audiences

This slide deck was developed to inform broader scientific, as well as general audiences about the role of the ocean in the global carbon cycle, including key sinks and sources of anthropogenic carbon and how they have evolved through time and space

Alginate inhibits iron absorption from ferrous gluconate in a randomized controlled trial and reduces iron uptake into Caco-2 cells

Previous in vitro results indicated that alginate beads might be a useful vehicle for food iron fortification. A human study was undertaken to test the hypothesis that alginate enhances iron absorption. A randomised, single blinded, cross-over trial was carried out in which iron absorption was measured from serum iron appearance after a test meal. Overnight-fasted volunteers (n=15) were given a test meal of 200g cola-flavoured jelly plus 21 mg iron as ferrous gluconate, either in alginate beads mixed into the jelly or in a capsule. Iron absorption was lower from the alginate beads than from ferrous gluconate (8.5% and 12.6% respectively, p=0.003). Sub-group B (n=9) consumed the test meals together with 600 mg calcium to determine whether alginate modified the inhibitory effect of calcium. Calcium reduced iron absorption from ferrous gluconate by 51%, from 11.5% to 5.6% (p=0.014), and from alginate beads by 37%, from 8.3% to 5.2% (p=0.009). In vitro studies using Caco-2 cells were designed to explore the reasons for the difference between the previous in vitro findings and the human study; confirmed the inhibitory effect of alginate. Beads similar to those used in the human study were subjected to simulated gastrointestinal digestion, with and without cola jelly, and the digestate applied to Caco-2 cells. Both alginate and cola jelly significantly reduced iron uptake into the cells, by 34% (p=0.009) and 35% (p=0.003) respectively. The combination of cola jelly and calcium produced a very low ferritin response, 16.5% (p<0.001) of that observed with ferrous gluconate alone. The results of these studies demonstrate that alginate beads are not a useful delivery system for soluble salts of iron for the purpose of food fortification

Mandeville, Bernard

Peer reviewe

Establishment of wMel Wolbachia in Aedes aegypti mosquitoes and reduction of local dengue transmission in Cairns and surrounding locations in northern Queensland, Australia.

Background: The wMel strain of Wolbachia has been successfully introduced into Aedes aegypti mosquitoes and subsequently shown in laboratory studies to reduce transmission of a range of viruses including dengue, Zika, chikungunya, yellow fever, and Mayaro viruses that cause human disease. Here we report the entomological and epidemiological outcomes of staged deployment of Wolbachia across nearly all significant dengue transmission risk areas in Australia. Methods: The  wMel strain of  Wolbachia was backcrossed into the local  Aedes aegypti genotype (Cairns and Townsville backgrounds) and mosquitoes were released in the field by staff or via community assisted methods. Mosquito monitoring was undertaken and mosquitoes were screened for the presence of  Wolbachia. Dengue case notifications were used to track dengue incidence in each location before and after releases. Results: Empirical analyses of the Wolbachia mosquito releases, including data on the density, frequency and duration of Wolbachia mosquito releases, indicate that Wolbachia can be readily established in local mosquito populations, using a variety of deployment options and over short release durations (mean release period 11 weeks, range 2-22 weeks). Importantly, Wolbachia frequencies have remained stable in mosquito populations since releases for up to 8 years. Analysis of dengue case notifications data demonstrates near-elimination of local dengue transmission for the past five years in locations where Wolbachia has been established. The regression model estimate of Wolbachia intervention effect from interrupted time series analyses of case notifications data prior to and after releases, indicated a 96% reduction in dengue incidence in Wolbachia treated populations (95% confidence interval: 84 - 99%). Conclusion: Deployment of the wMel strain of Wolbachia into local Ae. aegypti populations across the Australian regional cities of Cairns and most smaller regional communities with a past history of dengue has resulted in the reduction of local dengue transmission across all deployment areas