Bacterial Niche-Specific Genome Expansion Is Coupled with Highly Frequent Gene Disruptions in Deep-Sea Sediments

The complexity and dynamics of microbial metagenomes may be evaluated by genome size, gene duplication and the disruption rate between lineages. In this study, we pyrosequenced the metagenomes of microbes obtained from the brine and sediment of a deep-sea brine pool in the Red Sea to explore the possible genomic adaptations of the microbes in response to environmental changes. The microbes from the brine and sediments (both surface and deep layers) of the Atlantis II Deep brine pool had similar communities whereas the effective genome size varied from 7.4 Mb in the brine to more than 9 Mb in the sediment. This genome expansion in the sediment samples was due to gene duplication as evidenced by enrichment of the homologs. The duplicated genes were highly disrupted, on average by 47.6% and 70% for the surface and deep layers of the Atlantis II Deep sediment samples, respectively. The disruptive effects appeared to be mainly due to point mutations and frameshifts. In contrast, the homologs from the Atlantis II Deep brine sample were highly conserved and they maintained relatively small copy numbers. Likely, the adaptation of the microbes in the sediments was coupled with pseudogenizations and possibly functional diversifications of the paralogs in the expanded genomes. The maintenance of the pseudogenes in the large genomes is discussed

Galanin Receptor 1 Deletion Exacerbates Hippocampal Neuronal Loss after Systemic Kainate Administration in Mice

Galanin is a neuropeptide with a wide distribution in the central and peripheral nervous systems and whose physiological effects are mediated through three G protein-coupled receptor subtypes, GalR1, GalR2, and GalR3. Several lines of evidence indicate that galanin, as well as activation of the GalR1 receptor, is a potent and effective modulator of neuronal excitability in the hippocampus.In order to test more formally the potential influence of GalR1 on seizure-induced excitotoxic cell death, we conducted functional complementation tests in which transgenic mice that exhibit decreased expression of the GalR1 candidate mRNA underwent kainate-induced status epilepticus to determine if the quantitative trait of susceptibility to seizure-induced cell death is determined by the activity of GalR1. In the present study, we report that reduction of GalR1 mRNA via null mutation or injection of the GalR1 antagonist, galantide, prior to kainate-induced status epilepticus induces hippocampal damage in a mouse strain known to be highly resistant to kainate-induced neuronal injury. Wild-type and GalR1 knockout mice were subjected to systemic kainate administration. Seven days later, Nissl and NeuN immune- staining demonstrated that hippocampal cell death was significantly increased in GalR1 knockout strains and in animals injected with the GalR1 antagonist. Compared to GalR1-expressing mice, GalR1-deficient mice had significantly larger hippocampal lesions after status epilepticus.Our results suggest that a reduction of GalR1 expression in the C57BL/6J mouse strain renders them susceptible to excitotoxic injury following systemic kainate administration. From these results, GalR1 protein emerges as a new molecular target that may have a potential therapeutic value in modulating seizure-induced cell death

Iron Behaving Badly: Inappropriate Iron Chelation as a Major Contributor to the Aetiology of Vascular and Other Progressive Inflammatory and Degenerative Diseases

The production of peroxide and superoxide is an inevitable consequence of aerobic metabolism, and while these particular "reactive oxygen species" (ROSs) can exhibit a number of biological effects, they are not of themselves excessively reactive and thus they are not especially damaging at physiological concentrations. However, their reactions with poorly liganded iron species can lead to the catalytic production of the very reactive and dangerous hydroxyl radical, which is exceptionally damaging, and a major cause of chronic inflammation. We review the considerable and wide-ranging evidence for the involvement of this combination of (su)peroxide and poorly liganded iron in a large number of physiological and indeed pathological processes and inflammatory disorders, especially those involving the progressive degradation of cellular and organismal performance. These diseases share a great many similarities and thus might be considered to have a common cause (i.e. iron-catalysed free radical and especially hydroxyl radical generation). The studies reviewed include those focused on a series of cardiovascular, metabolic and neurological diseases, where iron can be found at the sites of plaques and lesions, as well as studies showing the significance of iron to aging and longevity. The effective chelation of iron by natural or synthetic ligands is thus of major physiological (and potentially therapeutic) importance. As systems properties, we need to recognise that physiological observables have multiple molecular causes, and studying them in isolation leads to inconsistent patterns of apparent causality when it is the simultaneous combination of multiple factors that is responsible. This explains, for instance, the decidedly mixed effects of antioxidants that have been observed, etc...Comment: 159 pages, including 9 Figs and 2184 reference

Accessing surgical care for pancreaticoduodenectomy: Patient variation in travel distance and choice to bypass hospitals to reach higher volume centers

BackgroundWhile better outcomes at high‐volume surgical centers have driven regionalization of complex surgical care, access to high‐volume centers often requires travel over longer distances. We sought to evaluate travel patterns of patients undergoing pancreaticoduodenectomy (PD) for pancreatic cancer to assess willingness of patients to travel for surgical care.MethodsThe California Office of Statewide Health Planning database was used to identify patients who underwent PD between 2005 and 2016. Total distance traveled, as well as whether a patient bypassed the nearest hospital that performed PD to get to a higher‐volume center was assessed. Multivariate analyses were used to identify factors associated with bypassing a local hospital for a higher‐volume center.ResultsAmong 23 014 patients who underwent PD, individuals traveled a median distance of 18.0 miles to get to a hospital that performed PD. The overwhelming majority (84%) of patients bypassed the nearest providing hospital and traveled a median additional 16.6 miles to their destination hospital. Among patients who bypassed the nearest hospital, 13,269 (68.6%) did so for a high‐volume destination hospital. Specifically, average annual PD volume at the nearest “bypassed” vs final destination hospital was 29.6 vs 56 cases, respectively. Outcomes at bypassed vs destination hospitals varied (incidence of complications: 39.2% vs 32.4%; failure‐to‐rescue: 14.5% vs 9.1%). PD at a high‐volume center was associated with lower mortality (OR = 0.46 95% CI, 0.22‐0.95). High‐volume PD ( > 20 cases) was predictive of hospital bypass (OR = 3.8 95% CI, 3.3‐4.4). Among patients who had surgery at a low‐volume center, nearly 20% bypassed a high‐volume hospital in route. Furthermore, among patients who did not bypass a high‐volume hospital, one‐third would have needed to travel only an additional 30 miles or less to reach the nearest high‐volume hospital.ConclusionMost patients undergoing PD bypassed the nearest providing hospital to seek care at a higher‐volume hospital. While these data reflect increased regionalization of complex surgical care, nearly 1 in 5 patients still underwent PD at a low‐volume center.Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/153129/1/jso25750.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/153129/2/jso25750_am.pd

Population pharmacokinetic modelling of rupatadine solution in 6–11 year olds and optimisation of the experimental design in younger children

AIMS:To optimise a pharmacokinetic (PK) study design of rupatadine for 2-5 year olds by using a population PK model developed with data from a study in 6-11 year olds. The design optimisation was driven by the need to avoid children's discomfort in the study. METHODS:PK data from 6-11 year olds with allergic rhinitis available from a previous study were used to construct a population PK model which we used in simulations to assess the dose to administer in a study in 2-5 year olds. In addition, an optimal design approach was used to determine the most appropriate number of sampling groups, sampling days, total samples and sampling times. RESULTS:A two-compartmental model with first-order absorption and elimination, with clearance dependent on weight adequately described the PK of rupatadine for 6-11 year olds. The dose selected for a trial in 2-5 year olds was 2.5 mg, as it provided a Cmax below the 3 ng/ml threshold. The optimal study design consisted of four groups of children (10 children each), a maximum sampling window of 2 hours in two clinic visits for drawing three samples on day 14 and one on day 28 coinciding with the final examination of the study. CONCLUSIONS:A PK study design was optimised in order to prioritise avoidance of discomfort for enrolled 2-5 year olds by taking only four blood samples from each child and minimising the length of hospital stays